@article{9336, abstract = {Mentorship is experience and/or knowledge‐based guidance. Mentors support, sponsor and advocate for mentees. Having one or more mentors when you seek advice can significantly influence and improve your research endeavours, well‐being and career development. Positive mentee–mentor relationships are vital for maintaining work–life balance and success in careers. Early‐career researchers (ECRs), in particular, can benefit from mentorship to navigate challenges in academic and nonacademic life and careers. Yet, strategies for selecting mentors and maintaining interactions with them are often underdiscussed within research environments. In this Words of Advice, we provide recommendations for ECRs to seek and manage mentorship interactions. Our article draws from our experiences as ECRs and published work, to provide suggestions for mentees to proactively promote beneficial mentorship interactions. The recommended practices highlight the importance of identifying mentorship needs, planning and selecting multiple and diverse mentors, setting goals, and maintaining constructive, and mutually beneficial working relationships with mentors.}, author = {Sarabipour, Sarvenaz and Hainer, Sarah J. and Arslan, Feyza N and De Winde, Charlotte M. and Furlong, Emily and Bielczyk, Natalia and Jadavji, Nafisa M. and Shah, Aparna P. and Davla, Sejal}, issn = {1742-4658}, journal = {FEBS Journal}, publisher = {Wiley}, title = {{Building and sustaining mentor interactions as a mentee}}, doi = {10.1111/febs.15823}, year = {2021}, } @article{9350, abstract = {Intercellular adhesion is the key to multicellularity, and its malfunction plays an important role in various developmental and disease-related processes. Although it has been intensively studied by both biologists and physicists, a commonly accepted definition of cell-cell adhesion is still being debated. Cell-cell adhesion has been described at the molecular scale as a function of adhesion receptors controlling binding affinity, at the cellular scale as resistance to detachment forces or modulation of surface tension, and at the tissue scale as a regulator of cellular rearrangements and morphogenesis. In this review, we aim to summarize and discuss recent advances in the molecular, cellular, and theoretical description of cell-cell adhesion, ranging from biomimetic models to the complexity of cells and tissues in an organismal context. In particular, we will focus on cadherin-mediated cell-cell adhesion and the role of adhesion signaling and mechanosensation therein, two processes central for understanding the biological and physical basis of cell-cell adhesion.}, author = {Arslan, Feyza N and Eckert, Julia and Schmidt, Thomas and Heisenberg, Carl-Philipp J}, issn = {1542-0086}, journal = {Biophysical Journal}, pages = {4182--4192}, publisher = {Biophysical Society}, title = {{Holding it together: when cadherin meets cadherin}}, doi = {10.1016/j.bpj.2021.03.025}, volume = {120}, year = {2021}, } @article{9759, author = {Bartlett, Michael John and Arslan, Feyza N and Bankston, Adriana and Sarabipour, Sarvenaz}, issn = {15537358}, journal = {PLoS Computational Biology}, number = {7}, publisher = {Public Library of Science}, title = {{Ten simple rules to improve academic work- life balance}}, doi = {10.1371/journal.pcbi.1009124}, volume = {17}, year = {2021}, } @article{9999, abstract = {The developmental strategies used by progenitor cells to endure a safe journey from their induction place towards the site of terminal differentiation are still poorly understood. Here we uncovered a progenitor cell allocation mechanism that stems from an incomplete process of epithelial delamination that allows progenitors to coordinate their movement with adjacent extra-embryonic tissues. Progenitors of the zebrafish laterality organ originate from the surface epithelial enveloping layer by an apical constriction process of cell delamination. During this process, progenitors retain long-term apical contacts that enable the epithelial layer to pull a subset of progenitors along their way towards the vegetal pole. The remaining delaminated progenitors follow apically-attached progenitors’ movement by a co-attraction mechanism, avoiding sequestration by the adjacent endoderm, ensuring their fate and collective allocation at the differentiation site. Thus, we reveal that incomplete delamination serves as a cellular platform for coordinated tissue movements during development. Impact Statement: Incomplete delamination serves as a cellular platform for coordinated tissue movements during development, guiding newly formed progenitor cell groups to the differentiation site.}, author = {Pulgar, Eduardo and Schwayer, Cornelia and Guerrero, Néstor and López, Loreto and Márquez, Susana and Härtel, Steffen and Soto, Rodrigo and Heisenberg, Carl Philipp and Concha, Miguel L.}, issn = {2050-084X}, journal = {eLife}, keywords = {cell delamination, apical constriction, dragging, mechanical forces, collective 18 locomotion, dorsal forerunner cells, zebrafish}, publisher = {eLife Sciences Publications}, title = {{Apical contacts stemming from incomplete delamination guide progenitor cell allocation through a dragging mechanism}}, doi = {10.7554/eLife.66483}, volume = {10}, year = {2021}, } @article{10202, abstract = {Zygotic genome activation (ZGA) initiates regionalized transcription underlying distinct cellular identities. ZGA is dependent upon dynamic chromatin architecture sculpted by conserved DNA-binding proteins. However, the direct mechanistic link between the onset of ZGA and the tissue-specific transcription remains unclear. Here, we have addressed the involvement of chromatin organizer Satb2 in orchestrating both processes during zebrafish embryogenesis. Integrative analysis of transcriptome, genome-wide occupancy and chromatin accessibility reveals contrasting molecular activities of maternally deposited and zygotically synthesized Satb2. Maternal Satb2 prevents premature transcription of zygotic genes by influencing the interplay between the pluripotency factors. By contrast, zygotic Satb2 activates transcription of the same group of genes during neural crest development and organogenesis. Thus, our comparative analysis of maternal versus zygotic function of Satb2 underscores how these antithetical activities are temporally coordinated and functionally implemented highlighting the evolutionary implications of the biphasic and bimodal regulation of landmark developmental transitions by a single determinant.}, author = {Pradhan, Saurabh J. and Reddy, Puli Chandramouli and Smutny, Michael and Sharma, Ankita and Sako, Keisuke and Oak, Meghana S. and Shah, Rini and Pal, Mrinmoy and Deshpande, Ojas and Dsilva, Greg and Tang, Yin and Mishra, Rakesh and Deshpande, Girish and Giraldez, Antonio J. and Sonawane, Mahendra and Heisenberg, Carl-Philipp J and Galande, Sanjeev}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Springer Nature}, title = {{Satb2 acts as a gatekeeper for major developmental transitions during early vertebrate embryogenesis}}, doi = {10.1038/s41467-021-26234-7}, volume = {12}, year = {2021}, } @article{10366, author = {Heisenberg, Carl-Philipp J and Lennon, Ana Maria and Mayor, Roberto and Salbreux, Guillaume}, issn = {2667-2901}, journal = {Cells and Development}, number = {12}, publisher = {Elsevier}, title = {{Special rebranding issue: “Quantitative cell and developmental biology”}}, doi = {10.1016/j.cdev.2021.203758}, volume = {168}, year = {2021}, } @article{10406, abstract = {Multicellular organisms develop complex shapes from much simpler, single-celled zygotes through a process commonly called morphogenesis. Morphogenesis involves an interplay between several factors, ranging from the gene regulatory networks determining cell fate and differentiation to the mechanical processes underlying cell and tissue shape changes. Thus, the study of morphogenesis has historically been based on multidisciplinary approaches at the interface of biology with physics and mathematics. Recent technological advances have further improved our ability to study morphogenesis by bridging the gap between the genetic and biophysical factors through the development of new tools for visualizing, analyzing, and perturbing these factors and their biochemical intermediaries. Here, we review how a combination of genetic, microscopic, biophysical, and biochemical approaches has aided our attempts to understand morphogenesis and discuss potential approaches that may be beneficial to such an inquiry in the future.}, author = {Mishra, Nikhil and Heisenberg, Carl-Philipp J}, issn = {1545-2948}, journal = {Annual Review of Genetics}, keywords = {morphogenesis, forward genetics, high-resolution microscopy, biophysics, biochemistry, patterning}, pages = {209--233}, publisher = {Annual Reviews}, title = {{Dissecting organismal morphogenesis by bridging genetics and biophysics}}, doi = {10.1146/annurev-genet-071819-103748}, volume = {55}, year = {2021}, } @article{10606, abstract = {Cell division orientation is thought to result from a competition between cell geometry and polarity domains controlling the position of the mitotic spindle during mitosis. Depending on the level of cell shape anisotropy or the strength of the polarity domain, one dominates the other and determines the orientation of the spindle. Whether and how such competition is also at work to determine unequal cell division (UCD), producing daughter cells of different size, remains unclear. Here, we show that cell geometry and polarity domains cooperate, rather than compete, in positioning the cleavage plane during UCDs in early ascidian embryos. We found that the UCDs and their orientation at the ascidian third cleavage rely on the spindle tilting in an anisotropic cell shape, and cortical polarity domains exerting different effects on spindle astral microtubules. By systematically varying mitotic cell shape, we could modulate the effect of attractive and repulsive polarity domains and consequently generate predicted daughter cell size asymmetries and position. We therefore propose that the spindle position during UCD is set by the combined activities of cell geometry and polarity domains, where cell geometry modulates the effect of cortical polarity domain(s).}, author = {Godard, Benoit G and Dumollard, Remi and Heisenberg, Carl-Philipp J and Mcdougall, Alex}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Combined effect of cell geometry and polarity domains determines the orientation of unequal division}}, doi = {10.7554/eLife.75639}, volume = {10}, year = {2021}, } @article{9298, abstract = {In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field. }, author = {Klionsky, Daniel J. and Abdel-Aziz, Amal Kamal and Abdelfatah, Sara and Abdellatif, Mahmoud and Abdoli, Asghar and Abel, Steffen and Abeliovich, Hagai and Abildgaard, Marie H. and Abudu, Yakubu Princely and Acevedo-Arozena, Abraham and Adamopoulos, Iannis E. and Adeli, Khosrow and Adolph, Timon E. and Adornetto, Annagrazia and Aflaki, Elma and Agam, Galila and Agarwal, Anupam and Aggarwal, Bharat B. and Agnello, Maria and Agostinis, Patrizia and Agrewala, Javed N. and Agrotis, Alexander and Aguilar, Patricia V. and Ahmad, S. Tariq and Ahmed, Zubair M. and Ahumada-Castro, Ulises and Aits, Sonja and Aizawa, Shu and Akkoc, Yunus and Akoumianaki, Tonia and Akpinar, Hafize Aysin and Al-Abd, Ahmed M. and Al-Akra, Lina and Al-Gharaibeh, Abeer and Alaoui-Jamali, Moulay A. and Alberti, Simon and Alcocer-Gómez, Elísabet and Alessandri, Cristiano and Ali, Muhammad and Alim Al-Bari, M. Abdul and Aliwaini, Saeb and Alizadeh, Javad and Almacellas, Eugènia and Almasan, Alexandru and Alonso, Alicia and Alonso, Guillermo D. and Altan-Bonnet, Nihal and Altieri, Dario C. and Álvarez, Élida M.C. and Alves, Sara and Alves Da Costa, Cristine and Alzaharna, Mazen M. and Amadio, Marialaura and Amantini, Consuelo and Amaral, Cristina and Ambrosio, Susanna and Amer, Amal O. and Ammanathan, Veena and An, Zhenyi and Andersen, Stig U. and Andrabi, Shaida A. and Andrade-Silva, Magaiver and Andres, Allen M. and Angelini, Sabrina and Ann, David and Anozie, Uche C. and Ansari, Mohammad Y. and Antas, Pedro and Antebi, Adam and Antón, Zuriñe and Anwar, Tahira and Apetoh, Lionel and Apostolova, Nadezda and Araki, Toshiyuki and Araki, Yasuhiro and Arasaki, Kohei and Araújo, Wagner L. and Araya, Jun and Arden, Catherine and Arévalo, Maria Angeles and Arguelles, Sandro and Arias, Esperanza and Arikkath, Jyothi and Arimoto, Hirokazu and Ariosa, Aileen R. and Armstrong-James, Darius and Arnauné-Pelloquin, Laetitia and Aroca, Angeles and Arroyo, Daniela S. and Arsov, Ivica and Artero, Rubén and Asaro, Dalia Maria Lucia and Aschner, Michael and Ashrafizadeh, Milad and Ashur-Fabian, Osnat and Atanasov, Atanas G. and Au, Alicia K. and Auberger, Patrick and Auner, Holger W. and Aurelian, Laure and Autelli, Riccardo and Avagliano, Laura and Ávalos, Yenniffer and Aveic, Sanja and Aveleira, Célia Alexandra and Avin-Wittenberg, Tamar and Aydin, Yucel and Ayton, Scott and Ayyadevara, Srinivas and Azzopardi, Maria and Baba, Misuzu and Backer, Jonathan M. and Backues, Steven K. and Bae, Dong Hun and Bae, Ok Nam and Bae, Soo Han and Baehrecke, Eric H. and Baek, Ahruem and Baek, Seung Hoon and Baek, Sung Hee and Bagetta, Giacinto and Bagniewska-Zadworna, Agnieszka and Bai, Hua and Bai, Jie and Bai, Xiyuan and Bai, Yidong and Bairagi, Nandadulal and Baksi, Shounak and Balbi, Teresa and Baldari, Cosima T. and Balduini, Walter and Ballabio, Andrea and Ballester, Maria and Balazadeh, Salma and Balzan, Rena and Bandopadhyay, Rina and Banerjee, Sreeparna and Banerjee, Sulagna and Bánréti, Ágnes and Bao, Yan and Baptista, Mauricio S. and Baracca, Alessandra and Barbati, Cristiana and Bargiela, Ariadna and Barilà, Daniela and Barlow, Peter G. and Barmada, Sami J. and Barreiro, Esther and Barreto, George E. and Bartek, Jiri and Bartel, Bonnie and Bartolome, Alberto and Barve, Gaurav R. and Basagoudanavar, Suresh H. and Bassham, Diane C. and Bast, Robert C. and Basu, Alakananda and Batoko, Henri and Batten, Isabella and Baulieu, Etienne E. and Baumgarner, Bradley L. and Bayry, Jagadeesh and Beale, Rupert and Beau, Isabelle and Beaumatin, Florian and Bechara, Luiz R.G. and Beck, George R. and Beers, Michael F. and Begun, Jakob and Behrends, Christian and Behrens, Georg M.N. and Bei, Roberto and Bejarano, Eloy and Bel, Shai and Behl, Christian and Belaid, Amine and Belgareh-Touzé, Naïma and Bellarosa, Cristina and Belleudi, Francesca and Belló Pérez, Melissa and Bello-Morales, Raquel and Beltran, Jackeline Soares De Oliveira and Beltran, Sebastián and Benbrook, Doris Mangiaracina and Bendorius, Mykolas and Benitez, Bruno A. and Benito-Cuesta, Irene and Bensalem, Julien and Berchtold, Martin W. and Berezowska, Sabina and Bergamaschi, Daniele and Bergami, Matteo and Bergmann, Andreas and Berliocchi, Laura and Berlioz-Torrent, Clarisse and Bernard, Amélie and Berthoux, Lionel and Besirli, Cagri G. and Besteiro, Sebastien and Betin, Virginie M. and Beyaert, Rudi and Bezbradica, Jelena S. and Bhaskar, Kiran and Bhatia-Kissova, Ingrid and Bhattacharya, Resham and Bhattacharya, Sujoy and Bhattacharyya, Shalmoli and Bhuiyan, Md Shenuarin and Bhutia, Sujit Kumar and Bi, Lanrong and Bi, Xiaolin and Biden, Trevor J. and Bijian, Krikor and Billes, Viktor A. and Binart, Nadine and Bincoletto, Claudia and Birgisdottir, Asa B. and Bjorkoy, Geir and Blanco, Gonzalo and Blas-Garcia, Ana and Blasiak, Janusz and Blomgran, Robert and Blomgren, Klas and Blum, Janice S. and Boada-Romero, Emilio and Boban, Mirta and Boesze-Battaglia, Kathleen and Boeuf, Philippe and Boland, Barry and Bomont, Pascale and Bonaldo, Paolo and Bonam, Srinivasa Reddy and Bonfili, Laura and Bonifacino, Juan S. and Boone, Brian A. and Bootman, Martin D. and Bordi, Matteo and Borner, Christoph and Bornhauser, Beat C. and Borthakur, Gautam and Bosch, Jürgen and Bose, Santanu and Botana, Luis M. and Botas, Juan and Boulanger, Chantal M. and Boulton, Michael E. and Bourdenx, Mathieu and Bourgeois, Benjamin and Bourke, Nollaig M. and Bousquet, Guilhem and Boya, Patricia and Bozhkov, Peter V. and Bozi, Luiz H.M. and Bozkurt, Tolga O. and Brackney, Doug E. and Brandts, Christian H. and Braun, Ralf J. and Braus, Gerhard H. and Bravo-Sagua, Roberto and Bravo-San Pedro, José M. and Brest, Patrick and Bringer, Marie Agnès and Briones-Herrera, Alfredo and Broaddus, V. Courtney and Brodersen, Peter and Brodsky, Jeffrey L. and Brody, Steven L. and Bronson, Paola G. and Bronstein, Jeff M. and Brown, Carolyn N. and Brown, Rhoderick E. and Brum, Patricia C. and Brumell, John H. and Brunetti-Pierri, Nicola and Bruno, Daniele and Bryson-Richardson, Robert J. and Bucci, Cecilia and Buchrieser, Carmen and Bueno, Marta and Buitrago-Molina, Laura Elisa and Buraschi, Simone and Buch, Shilpa and Buchan, J. Ross and Buckingham, Erin M. and Budak, Hikmet and Budini, Mauricio and Bultynck, Geert and Burada, Florin and Burgoyne, Joseph R. and Burón, M. Isabel and Bustos, Victor and Büttner, Sabrina and Butturini, Elena and Byrd, Aaron and Cabas, Isabel and Cabrera-Benitez, Sandra and Cadwell, Ken and Cai, Jingjing and Cai, Lu and Cai, Qian and Cairó, Montserrat and Calbet, Jose A. and Caldwell, Guy A. and Caldwell, Kim A. and Call, Jarrod A. and Calvani, Riccardo and Calvo, Ana C. and Calvo-Rubio Barrera, Miguel and Camara, Niels O.S. and Camonis, Jacques H. and Camougrand, Nadine and Campanella, Michelangelo and Campbell, Edward M. and Campbell-Valois, François Xavier and Campello, Silvia and Campesi, Ilaria and Campos, Juliane C. and Camuzard, Olivier and Cancino, Jorge and Candido De Almeida, Danilo and Canesi, Laura and Caniggia, Isabella and Canonico, Barbara and Cantí, Carles and Cao, Bin and Caraglia, Michele and Caramés, Beatriz and Carchman, Evie H. and Cardenal-Muñoz, Elena and Cardenas, Cesar and Cardenas, Luis and Cardoso, Sandra M. and Carew, Jennifer S. and Carle, Georges F. and Carleton, Gillian and Carloni, Silvia and Carmona-Gutierrez, Didac and Carneiro, Leticia A. and Carnevali, Oliana and Carosi, Julian M. and Carra, Serena and Carrier, Alice and Carrier, Lucie and Carroll, Bernadette and Carter, A. Brent and Carvalho, Andreia Neves and Casanova, Magali and Casas, Caty and Casas, Josefina and Cassioli, Chiara and Castillo, Eliseo F. and Castillo, Karen and Castillo-Lluva, Sonia and Castoldi, Francesca and Castori, Marco and Castro, Ariel F. and Castro-Caldas, Margarida and Castro-Hernandez, Javier and Castro-Obregon, Susana and Catz, Sergio D. and Cavadas, Claudia and Cavaliere, Federica and Cavallini, Gabriella and Cavinato, Maria and Cayuela, Maria L. and Cebollada Rica, Paula and Cecarini, Valentina and Cecconi, Francesco and Cechowska-Pasko, Marzanna and Cenci, Simone and Ceperuelo-Mallafré, Victòria and Cerqueira, João J. and Cerutti, Janete M. and Cervia, Davide and Cetintas, Vildan Bozok and Cetrullo, Silvia and Chae, Han Jung and Chagin, Andrei S. and Chai, Chee Yin and Chakrabarti, Gopal and Chakrabarti, Oishee and Chakraborty, Tapas and Chakraborty, Trinad and Chami, Mounia and Chamilos, Georgios and Chan, David W. and Chan, Edmond Y.W. and Chan, Edward D. and Chan, H. Y.Edwin and Chan, Helen H. and Chan, Hung and Chan, Matthew T.V. and Chan, Yau Sang and Chandra, Partha K. and Chang, Chih Peng and Chang, Chunmei and Chang, Hao Chun and Chang, Kai and Chao, Jie and Chapman, Tracey and Charlet-Berguerand, Nicolas and Chatterjee, Samrat and Chaube, Shail K. and Chaudhary, Anu and Chauhan, Santosh and Chaum, Edward and Checler, Frédéric and Cheetham, Michael E. and Chen, Chang Shi and Chen, Guang Chao and Chen, Jian Fu and Chen, Liam L. and Chen, Leilei and Chen, Lin and Chen, Mingliang and Chen, Mu Kuan and Chen, Ning and Chen, Quan and Chen, Ruey Hwa and Chen, Shi and Chen, Wei and Chen, Weiqiang and Chen, Xin Ming and Chen, Xiong Wen and Chen, Xu and Chen, Yan and Chen, Ye Guang and Chen, Yingyu and Chen, Yongqiang and Chen, Yu Jen and Chen, Yue Qin and Chen, Zhefan Stephen and Chen, Zhi and Chen, Zhi Hua and Chen, Zhijian J. and Chen, Zhixiang and Cheng, Hanhua and Cheng, Jun and Cheng, Shi Yuan and Cheng, Wei and Cheng, Xiaodong and Cheng, Xiu Tang and Cheng, Yiyun and Cheng, Zhiyong and Chen, Zhong and Cheong, Heesun and Cheong, Jit Kong and Chernyak, Boris V. and Cherry, Sara and Cheung, Chi Fai Randy and Cheung, Chun Hei Antonio and Cheung, King Ho and Chevet, Eric and Chi, Richard J. and Chiang, Alan Kwok Shing and Chiaradonna, Ferdinando and Chiarelli, Roberto and Chiariello, Mario and Chica, Nathalia and Chiocca, Susanna and Chiong, Mario and Chiou, Shih Hwa and Chiramel, Abhilash I. and Chiurchiù, Valerio and Cho, Dong Hyung and Choe, Seong Kyu and Choi, Augustine M.K. and Choi, Mary E. and Choudhury, Kamalika Roy and Chow, Norman S. and Chu, Charleen T. and Chua, Jason P. and Chua, John Jia En and Chung, Hyewon and Chung, Kin Pan and Chung, Seockhoon and Chung, So Hyang and Chung, Yuen Li and Cianfanelli, Valentina and Ciechomska, Iwona A. and Cifuentes, Mariana and Cinque, Laura and Cirak, Sebahattin and Cirone, Mara and Clague, Michael J. and Clarke, Robert and Clementi, Emilio and Coccia, Eliana M. and Codogno, Patrice and Cohen, Ehud and Cohen, Mickael M. and Colasanti, Tania and Colasuonno, Fiorella and Colbert, Robert A. and Colell, Anna and Čolić, Miodrag and Coll, Nuria S. and Collins, Mark O. and Colombo, María I. and Colón-Ramos, Daniel A. and Combaret, Lydie and Comincini, Sergio and Cominetti, Márcia R. and Consiglio, Antonella and Conte, Andrea and Conti, Fabrizio and Contu, Viorica Raluca and Cookson, Mark R. and Coombs, Kevin M. and Coppens, Isabelle and Corasaniti, Maria Tiziana and Corkery, Dale P. and Cordes, Nils and Cortese, Katia and Costa, Maria Do Carmo and Costantino, Sarah and Costelli, Paola and Coto-Montes, Ana and Crack, Peter J. and Crespo, Jose L. and Criollo, Alfredo and Crippa, Valeria and Cristofani, Riccardo and Csizmadia, Tamas and Cuadrado, Antonio and Cui, Bing and Cui, Jun and Cui, Yixian and Cui, Yong and Culetto, Emmanuel and Cumino, Andrea C. and Cybulsky, Andrey V. and Czaja, Mark J. and Czuczwar, Stanislaw J. and D’Adamo, Stefania and D’Amelio, Marcello and D’Arcangelo, Daniela and D’Lugos, Andrew C. and D’Orazi, Gabriella and Da Silva, James A. and Dafsari, Hormos Salimi and Dagda, Ruben K. and Dagdas, Yasin and Daglia, Maria and Dai, Xiaoxia and Dai, Yun and Dai, Yuyuan and Dal Col, Jessica and Dalhaimer, Paul and Dalla Valle, Luisa and Dallenga, Tobias and Dalmasso, Guillaume and Damme, Markus and Dando, Ilaria and Dantuma, Nico P. and Darling, April L. and Das, Hiranmoy and Dasarathy, Srinivasan and Dasari, Santosh K. and Dash, Srikanta and Daumke, Oliver and Dauphinee, Adrian N. and Davies, Jeffrey S. and Dávila, Valeria A. and Davis, Roger J. and Davis, Tanja and Dayalan Naidu, Sharadha and De Amicis, Francesca and De Bosscher, Karolien and De Felice, Francesca and De Franceschi, Lucia and De Leonibus, Chiara and De Mattos Barbosa, Mayara G. and De Meyer, Guido R.Y. and De Milito, Angelo and De Nunzio, Cosimo and De Palma, Clara and De Santi, Mauro and De Virgilio, Claudio and De Zio, Daniela and Debnath, Jayanta and Debosch, Brian J. and Decuypere, Jean Paul and Deehan, Mark A. and Deflorian, Gianluca and Degregori, James and Dehay, Benjamin and Del Rio, Gabriel and Delaney, Joe R. and Delbridge, Lea M.D. and Delorme-Axford, Elizabeth and Delpino, M. Victoria and Demarchi, Francesca and Dembitz, Vilma and Demers, Nicholas D. and Deng, Hongbin and Deng, Zhiqiang and Dengjel, Joern and Dent, Paul and Denton, Donna and Depamphilis, Melvin L. and Der, Channing J. and Deretic, Vojo and Descoteaux, Albert and Devis, Laura and Devkota, Sushil and Devuyst, Olivier and Dewson, Grant and Dharmasivam, Mahendiran and Dhiman, Rohan and Di Bernardo, Diego and Di Cristina, Manlio and Di Domenico, Fabio and Di Fazio, Pietro and Di Fonzo, Alessio and Di Guardo, Giovanni and Di Guglielmo, Gianni M. and Di Leo, Luca and Di Malta, Chiara and Di Nardo, Alessia and Di Rienzo, Martina and Di Sano, Federica and Diallinas, George and Diao, Jiajie and Diaz-Araya, Guillermo and Díaz-Laviada, Inés and Dickinson, Jared M. and Diederich, Marc and Dieudé, Mélanie and Dikic, Ivan and Ding, Shiping and Ding, Wen Xing and Dini, Luciana and Dinić, Jelena and Dinic, Miroslav and Dinkova-Kostova, Albena T. and Dionne, Marc S. and Distler, Jörg H.W. and Diwan, Abhinav and Dixon, Ian M.C. and Djavaheri-Mergny, Mojgan and Dobrinski, Ina and Dobrovinskaya, Oxana and Dobrowolski, Radek and Dobson, Renwick C.J. and Đokić, Jelena and Dokmeci Emre, Serap and Donadelli, Massimo and Dong, Bo and Dong, Xiaonan and Dong, Zhiwu and Dorn, Gerald W. and Dotsch, Volker and Dou, Huan and Dou, Juan and Dowaidar, Moataz and Dridi, Sami and Drucker, Liat and Du, Ailian and Du, Caigan and Du, Guangwei and Du, Hai Ning and Du, Li Lin and Du Toit, André and Duan, Shao Bin and Duan, Xiaoqiong and Duarte, Sónia P. and Dubrovska, Anna and Dunlop, Elaine A. and Dupont, Nicolas and Durán, Raúl V. and Dwarakanath, Bilikere S. and Dyshlovoy, Sergey A. and Ebrahimi-Fakhari, Darius and Eckhart, Leopold and Edelstein, Charles L. and Efferth, Thomas and Eftekharpour, Eftekhar and Eichinger, Ludwig and Eid, Nabil and Eisenberg, Tobias and Eissa, N. Tony and Eissa, Sanaa and Ejarque, Miriam and El Andaloussi, Abdeljabar and El-Hage, Nazira and El-Naggar, Shahenda and Eleuteri, Anna Maria and El-Shafey, Eman S. and Elgendy, Mohamed and Eliopoulos, Aristides G. and Elizalde, María M. and Elks, Philip M. and Elsasser, Hans Peter and Elsherbiny, Eslam S. and Emerling, Brooke M. and Emre, N. C.Tolga and Eng, Christina H. and Engedal, Nikolai and Engelbrecht, Anna Mart and Engelsen, Agnete S.T. and Enserink, Jorrit M. and Escalante, Ricardo and Esclatine, Audrey and Escobar-Henriques, Mafalda and Eskelinen, Eeva Liisa and Espert, Lucile and Eusebio, Makandjou Ola and Fabrias, Gemma and Fabrizi, Cinzia and Facchiano, Antonio and Facchiano, Francesco and Fadeel, Bengt and Fader, Claudio and Faesen, Alex C. and Fairlie, W. Douglas and Falcó, Alberto and Falkenburger, Bjorn H. and Fan, Daping and Fan, Jie and Fan, Yanbo and Fang, Evandro F. and Fang, Yanshan and Fang, Yognqi and Fanto, Manolis and Farfel-Becker, Tamar and Faure, Mathias and Fazeli, Gholamreza and Fedele, Anthony O. and Feldman, Arthur M. and Feng, Du and Feng, Jiachun and Feng, Lifeng and Feng, Yibin and Feng, Yuchen and Feng, Wei and Fenz Araujo, Thais and Ferguson, Thomas A. and Fernández, Álvaro F. and Fernandez-Checa, Jose C. and Fernández-Veledo, Sonia and Fernie, Alisdair R. and Ferrante, Anthony W. and Ferraresi, Alessandra and Ferrari, Merari F. and Ferreira, Julio C.B. and Ferro-Novick, Susan and Figueras, Antonio and Filadi, Riccardo and Filigheddu, Nicoletta and Filippi-Chiela, Eduardo and Filomeni, Giuseppe and Fimia, Gian Maria and Fineschi, Vittorio and Finetti, Francesca and Finkbeiner, Steven and Fisher, Edward A. and Fisher, Paul B. and Flamigni, Flavio and Fliesler, Steven J. and Flo, Trude H. and Florance, Ida and Florey, Oliver and Florio, Tullio and Fodor, Erika and Follo, Carlo and Fon, Edward A. and Forlino, Antonella and Fornai, Francesco and Fortini, Paola and Fracassi, Anna and Fraldi, Alessandro and Franco, Brunella and Franco, Rodrigo and Franconi, Flavia and Frankel, Lisa B. and Friedman, Scott L. and Fröhlich, Leopold F. and Frühbeck, Gema and Fuentes, Jose M. and Fujiki, Yukio and Fujita, Naonobu and Fujiwara, Yuuki and Fukuda, Mitsunori and Fulda, Simone and Furic, Luc and Furuya, Norihiko and Fusco, Carmela and Gack, Michaela U. and Gaffke, Lidia and Galadari, Sehamuddin and Galasso, Alessia and Galindo, Maria F. and Gallolu Kankanamalage, Sachith and Galluzzi, Lorenzo and Galy, Vincent and Gammoh, Noor and Gan, Boyi and Ganley, Ian G. and Gao, Feng and Gao, Hui and Gao, Minghui and Gao, Ping and Gao, Shou Jiang and Gao, Wentao and Gao, Xiaobo and Garcera, Ana and Garcia, Maria Noé and Garcia, Verónica E. and García-Del Portillo, Francisco and Garcia-Escudero, Vega and 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and Golebiewska, Anna and Gomes, Luciana R. and Gomez, Rodrigo and Gómez-Sánchez, Rubén and Gomez-Puerto, Maria Catalina and Gomez-Sintes, Raquel and Gong, Qingqiu and Goni, Felix M. and González-Gallego, Javier and Gonzalez-Hernandez, Tomas and Gonzalez-Polo, Rosa A. and Gonzalez-Reyes, Jose A. and González-Rodríguez, Patricia and Goping, Ing Swie and Gorbatyuk, Marina S. and Gorbunov, Nikolai V. and Görgülü, Kıvanç and Gorojod, Roxana M. and Gorski, Sharon M. and Goruppi, Sandro and Gotor, Cecilia and Gottlieb, Roberta A. and Gozes, Illana and Gozuacik, Devrim and Graef, Martin and Gräler, Markus H. and Granatiero, Veronica and Grasso, Daniel and Gray, Joshua P. and Green, Douglas R. and Greenhough, Alexander and Gregory, Stephen L. and Griffin, Edward F. and Grinstaff, Mark W. and Gros, Frederic and Grose, Charles and Gross, Angelina S. and Gruber, Florian and Grumati, Paolo and Grune, Tilman and Gu, Xueyan and Guan, Jun Lin and Guardia, Carlos M. and Guda, Kishore and Guerra, Flora 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and Kanthasamy, Anumantha G. and Kanthasamy, Arthi and Kantorow, Marc and Kapuy, Orsolya and Karamouzis, Michalis V. and Karim, Md Razaul and Karmakar, Parimal and Katare, Rajesh G. and Kato, Masaru and Kaufmann, Stefan H.E. and Kauppinen, Anu and Kaushal, Gur P. and Kaushik, Susmita and Kawasaki, Kiyoshi and Kazan, Kemal and Ke, Po Yuan and Keating, Damien J. and Keber, Ursula and Kehrl, John H. and Keller, Kate E. and Keller, Christian W. and Kemper, Jongsook Kim and Kenific, Candia M. and Kepp, Oliver and Kermorgant, Stephanie and Kern, Andreas and Ketteler, Robin and Keulers, Tom G. and Khalfin, Boris and Khalil, Hany and Khambu, Bilon and Khan, Shahid Y. and Khandelwal, Vinoth Kumar Megraj and Khandia, Rekha and Kho, Widuri and Khobrekar, Noopur V. and Khuansuwan, Sataree and Khundadze, Mukhran and Killackey, Samuel A. and Kim, Dasol and Kim, Deok Ryong and Kim, Do Hyung and Kim, Dong Eun and Kim, Eun Young and Kim, Eun Kyoung and Kim, Hak Rim and Kim, Hee Sik and Hyung-Ryong Kim, Unknown and Kim, Jeong Hun and Kim, Jin Kyung and Kim, Jin Hoi and Kim, Joungmok and Kim, Ju Hwan and Kim, Keun Il and Kim, Peter K. and Kim, Seong Jun and Kimball, Scot R. and Kimchi, Adi and Kimmelman, Alec C. and Kimura, Tomonori and King, Matthew A. and Kinghorn, Kerri J. and Kinsey, Conan G. and Kirkin, Vladimir and Kirshenbaum, Lorrie A. and Kiselev, Sergey L. and Kishi, Shuji and Kitamoto, Katsuhiko and Kitaoka, Yasushi and Kitazato, Kaio and Kitsis, Richard N. and Kittler, Josef T. and Kjaerulff, Ole and Klein, Peter S. and Klopstock, Thomas and Klucken, Jochen and Knævelsrud, Helene and Knorr, Roland L. and Ko, Ben C.B. and Ko, Fred and Ko, Jiunn Liang and Kobayashi, Hotaka and Kobayashi, Satoru and Koch, Ina and Koch, Jan C. and Koenig, Ulrich and Kögel, Donat and Koh, Young Ho and Koike, Masato and Kohlwein, Sepp D. and Kocaturk, Nur M. and Komatsu, Masaaki and König, Jeannette and Kono, Toru and Kopp, Benjamin T. and Korcsmaros, Tamas and Korkmaz, Gözde and Korolchuk, 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and Lai, Zhibing and Laird, Angela S. and Lakkaraju, Aparna and Lamark, Trond and Lan, Sheng Hui and Landajuela, Ane and Lane, Darius J.R. and Lane, Jon D. and Lang, Charles H. and Lange, Carsten and Langel, Ülo and Langer, Rupert and Lapaquette, Pierre and Laporte, Jocelyn and Larusso, Nicholas F. and Lastres-Becker, Isabel and Lau, Wilson Chun Yu and Laurie, Gordon W. and Lavandero, Sergio and Law, Betty Yuen Kwan and Law, Helen Ka Wai and Layfield, Rob and Le, Weidong and Le Stunff, Herve and Leary, Alexandre Y. and Lebrun, Jean Jacques and Leck, Lionel Y.W. and Leduc-Gaudet, Jean Philippe and Lee, Changwook and Lee, Chung Pei and Lee, Da Hye and Lee, Edward B. and Lee, Erinna F. and Lee, Gyun Min and Lee, He Jin and Lee, Heung Kyu and Lee, Jae Man and Lee, Jason S. and Lee, Jin A. and Lee, Joo Yong and Lee, Jun Hee and Lee, Michael and Lee, Min Goo and Lee, Min Jae and Lee, Myung Shik and Lee, Sang Yoon and Lee, Seung Jae and Lee, Stella Y. and Lee, Sung Bae and Lee, Won Hee and 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Guanghong and Liao, Lujian and Liao, Mingzhi and Liao, Yung Feng and Librizzi, Mariangela and Lie, Pearl P.Y. and Lilly, Mary A. and Lim, Hyunjung J. and Lima, Thania R.R. and Limana, Federica and Lin, Chao and Lin, Chih Wen and Lin, Dar Shong and Lin, Fu Cheng and Lin, Jiandie D. and Lin, Kurt M. and Lin, Kwang Huei and Lin, Liang Tzung and Lin, Pei Hui and Lin, Qiong and Lin, Shaofeng and Lin, Su Ju and Lin, Wenyu and Lin, Xueying and Lin, Yao Xin and Lin, Yee Shin and Linden, Rafael and Lindner, Paula and Ling, Shuo Chien and Lingor, Paul and Linnemann, Amelia K. and Liou, Yih Cherng and Lipinski, Marta M. and Lipovšek, Saška and Lira, Vitor A. and Lisiak, Natalia and Liton, Paloma B. and Liu, Chao and Liu, Ching Hsuan and Liu, Chun Feng and Liu, Cui Hua and Liu, Fang and Liu, Hao and Liu, Hsiao Sheng and Liu, Hua Feng and Liu, Huifang and Liu, Jia and Liu, Jing and Liu, Julia and Liu, Leyuan and Liu, Longhua and Liu, Meilian and Liu, Qin and Liu, Wei and Liu, Wende and Liu, Xiao 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Memisoglu, Gonen and Mendes, Alexandrina F. and Meng, Delong and Meng, Fei and Meng, Tian and Menna-Barreto, Rubem and Menon, Manoj B. and Mercer, Carol and Mercier, Anne E. and Mergny, Jean Louis and Merighi, Adalberto and Merkley, Seth D. and Merla, Giuseppe and Meske, Volker and Mestre, Ana Cecilia and Metur, Shree Padma and Meyer, Christian and Meyer, Hemmo and Mi, Wenyi and Mialet-Perez, Jeanne and Miao, Junying and Micale, Lucia and Miki, Yasuo and Milan, Enrico and Milczarek, Małgorzata and Miller, Dana L. and Miller, Samuel I. and Miller, Silke and Millward, Steven W. and Milosevic, Ira and Minina, Elena A. and Mirzaei, Hamed and Mirzaei, Hamid Reza and Mirzaei, Mehdi and Mishra, Amit and Mishra, Nandita and Mishra, Paras Kumar and Misirkic Marjanovic, Maja and Misasi, Roberta and Misra, Amit and Misso, Gabriella and Mitchell, Claire and Mitou, Geraldine and Miura, Tetsuji and Miyamoto, Shigeki and Miyazaki, Makoto and Miyazaki, Mitsunori and Miyazaki, Taiga and Miyazawa, Keisuke and Mizushima, Noboru and Mogensen, Trine H. and Mograbi, Baharia and Mohammadinejad, Reza and Mohamud, Yasir and Mohanty, Abhishek and Mohapatra, Sipra and Möhlmann, Torsten and Mohmmed, Asif and Moles, Anna and Moley, Kelle H. and Molinari, Maurizio and Mollace, Vincenzo and Møller, Andreas Buch and Mollereau, Bertrand and Mollinedo, Faustino and Montagna, Costanza and Monteiro, Mervyn J. and Montella, Andrea and Montes, L. Ruth and Montico, Barbara and Mony, Vinod K. and Monzio Compagnoni, Giacomo and Moore, Michael N. and Moosavi, Mohammad A. and Mora, Ana L. and Mora, Marina and Morales-Alamo, David and Moratalla, Rosario and Moreira, Paula I. and Morelli, Elena and Moreno, Sandra and Moreno-Blas, Daniel and Moresi, Viviana and Morga, Benjamin and Morgan, Alwena H. and Morin, Fabrice and Morishita, Hideaki and Moritz, Orson L. and Moriyama, Mariko and Moriyasu, Yuji and Morleo, Manuela and Morselli, Eugenia and Moruno-Manchon, Jose F. and Moscat, Jorge and Mostowy, Serge and Motori, Elisa and Moura, Andrea Felinto and Moustaid-Moussa, Naima and Mrakovcic, Maria and Muciño-Hernández, Gabriel and Mukherjee, Anupam and Mukhopadhyay, Subhadip and Mulcahy Levy, Jean M. and Mulero, Victoriano and Muller, Sylviane and Münch, Christian and Munjal, Ashok and Munoz-Canoves, Pura and Muñoz-Galdeano, Teresa and Münz, Christian and Murakawa, Tomokazu and Muratori, Claudia and Murphy, Brona M. and Murphy, J. Patrick and Murthy, Aditya and Myöhänen, Timo T. and Mysorekar, Indira U. and Mytych, Jennifer and Nabavi, Seyed Mohammad and Nabissi, Massimo and Nagy, Péter and Nah, Jihoon and Nahimana, Aimable and Nakagawa, Ichiro and Nakamura, Ken and Nakatogawa, Hitoshi and Nandi, Shyam S. and Nanjundan, Meera and Nanni, Monica and Napolitano, Gennaro and Nardacci, Roberta and Narita, Masashi and Nassif, Melissa and Nathan, Ilana and Natsumeda, Manabu and Naude, Ryno J. and Naumann, Christin and Naveiras, Olaia and Navid, Fatemeh and Nawrocki, Steffan T. and Nazarko, Taras Y. and Nazio, Francesca and Negoita, Florentina and Neill, Thomas and Neisch, Amanda L. and Neri, Luca M. and Netea, Mihai G. and Neubert, Patrick and Neufeld, Thomas P. and Neumann, Dietbert and Neutzner, Albert and Newton, Phillip T. and Ney, Paul A. and Nezis, Ioannis P. and Ng, Charlene C.W. and Ng, Tzi Bun and Nguyen, Hang T.T. and Nguyen, Long T. and Ni, Hong Min and Ní Cheallaigh, Clíona and Ni, Zhenhong and Nicolao, M. Celeste and Nicoli, Francesco and Nieto-Diaz, Manuel and Nilsson, Per and Ning, Shunbin and Niranjan, Rituraj and Nishimune, Hiroshi and Niso-Santano, Mireia and Nixon, Ralph A. and Nobili, Annalisa and Nobrega, Clevio and Noda, Takeshi and Nogueira-Recalde, Uxía and Nolan, Trevor M. and Nombela, Ivan and Novak, Ivana and Novoa, Beatriz and Nozawa, Takashi and Nukina, Nobuyuki and Nussbaum-Krammer, Carmen and Nylandsted, Jesper and O’Donovan, Tracey R. and O’Leary, Seónadh M. and O’Rourke, Eyleen J. and O’Sullivan, Mary P. and O’Sullivan, Timothy E. and Oddo, Salvatore and Oehme, Ina and Ogawa, Michinaga and Ogier-Denis, Eric and Ogmundsdottir, Margret H. and Ogretmen, Besim and Oh, Goo Taeg and Oh, Seon Hee and Oh, Young J. and Ohama, Takashi and Ohashi, Yohei and Ohmuraya, Masaki and Oikonomou, Vasileios and Ojha, Rani and Okamoto, Koji and Okazawa, Hitoshi and Oku, Masahide and Oliván, Sara and Oliveira, Jorge M.A. and Ollmann, Michael and Olzmann, James A. and Omari, Shakib and Omary, M. Bishr and Önal, Gizem and Ondrej, Martin and Ong, Sang Bing and Ong, Sang Ging and Onnis, Anna and Orellana, Juan A. and Orellana-Muñoz, Sara and Ortega-Villaizan, Maria Del Mar and Ortiz-Gonzalez, Xilma R. and Ortona, Elena and Osiewacz, Heinz D. and Osman, Abdel Hamid K. and Osta, Rosario and Otegui, Marisa S. and Otsu, Kinya and Ott, Christiane and Ottobrini, Luisa and Ou, Jing Hsiung James and Outeiro, Tiago F. and Oynebraten, Inger and Ozturk, Melek and Pagès, Gilles and Pahari, Susanta and Pajares, Marta and Pajvani, Utpal B. and Pal, Rituraj and Paladino, Simona and Pallet, Nicolas and Palmieri, Michela and Palmisano, Giuseppe and Palumbo, Camilla and Pampaloni, Francesco and Pan, Lifeng and Pan, Qingjun and Pan, Wenliang and Pan, Xin and Panasyuk, Ganna and Pandey, Rahul and Pandey, Udai B. and Pandya, Vrajesh and Paneni, Francesco and Pang, Shirley Y. and Panzarini, Elisa and Papademetrio, Daniela L. and Papaleo, Elena and Papinski, Daniel and Papp, Diana and Park, Eun Chan and Park, Hwan Tae and Park, Ji Man and Park, Jong In and Park, Joon Tae and Park, Junsoo and Park, Sang Chul and Park, Sang Youel and Parola, Abraham H. and Parys, Jan B. and Pasquier, Adrien and Pasquier, Benoit and Passos, João F. and Pastore, Nunzia and Patel, Hemal H. and Patschan, Daniel and Pattingre, Sophie and Pedraza-Alva, Gustavo and Pedraza-Chaverri, Jose and Pedrozo, Zully and Pei, Gang and Pei, Jianming and Peled-Zehavi, Hadas and Pellegrini, Joaquín M. and Pelletier, Joffrey and Peñalva, Miguel A. and Peng, Di and Peng, Ying and Penna, Fabio and Pennuto, Maria and Pentimalli, Francesca and Pereira, Cláudia M.F. and Pereira, Gustavo J.S. and Pereira, Lilian C. and Pereira De Almeida, Luis and Perera, Nirma D. and Pérez-Lara, Ángel and Perez-Oliva, Ana B. and Pérez-Pérez, María Esther and Periyasamy, Palsamy and Perl, Andras and Perrotta, Cristiana and Perrotta, Ida and Pestell, Richard G. and Petersen, Morten and Petrache, Irina and Petrovski, Goran and Pfirrmann, Thorsten and Pfister, Astrid S. and Philips, Jennifer A. and Pi, Huifeng and Picca, Anna and Pickrell, Alicia M. and Picot, Sandy and Pierantoni, Giovanna M. and Pierdominici, Marina and Pierre, Philippe and Pierrefite-Carle, Valérie and Pierzynowska, Karolina and Pietrocola, Federico and Pietruczuk, Miroslawa and Pignata, Claudio and Pimentel-Muiños, Felipe X. and Pinar, Mario and Pinheiro, Roberta O. and Pinkas-Kramarski, Ronit and Pinton, Paolo and Pircs, Karolina and Piya, Sujan and Pizzo, Paola and Plantinga, Theo S. and Platta, Harald W. and Plaza-Zabala, Ainhoa and Plomann, Markus and Plotnikov, Egor Y. and Plun-Favreau, Helene and Pluta, Ryszard and Pocock, Roger and Pöggeler, Stefanie and Pohl, Christian and Poirot, Marc and Poletti, Angelo and Ponpuak, Marisa and Popelka, Hana and Popova, Blagovesta and Porta, Helena and Porte Alcon, Soledad and Portilla-Fernandez, Eliana and Post, Martin and Potts, Malia B. and Poulton, Joanna and Powers, Ted and Prahlad, Veena and Prajsnar, Tomasz K. and Praticò, Domenico and Prencipe, Rosaria and Priault, Muriel and Proikas-Cezanne, Tassula and Promponas, Vasilis J. and Proud, Christopher G. and Puertollano, Rosa and Puglielli, Luigi and Pulinilkunnil, Thomas and Puri, Deepika and Puri, Rajat and Puyal, Julien and Qi, Xiaopeng and Qi, Yongmei and Qian, Wenbin and Qiang, Lei and Qiu, Yu and Quadrilatero, Joe and Quarleri, Jorge and Raben, Nina and Rabinowich, Hannah and Ragona, Debora and Ragusa, Michael J. and Rahimi, Nader and Rahmati, Marveh and Raia, Valeria and Raimundo, Nuno and Rajasekaran, Namakkal Soorappan and Ramachandra Rao, Sriganesh and Rami, Abdelhaq and Ramírez-Pardo, Ignacio and Ramsden, David B. and Randow, Felix and Rangarajan, Pundi N. and Ranieri, Danilo and Rao, Hai and Rao, Lang and Rao, Rekha and Rathore, Sumit and Ratnayaka, J. Arjuna and Ratovitski, Edward A. and Ravanan, Palaniyandi and Ravegnini, Gloria and Ray, Swapan K. and Razani, Babak and Rebecca, Vito and Reggiori, Fulvio and Régnier-Vigouroux, Anne and Reichert, Andreas S. and Reigada, David and Reiling, Jan H. and Rein, Theo and Reipert, Siegfried and Rekha, Rokeya Sultana and Ren, Hongmei and Ren, Jun and Ren, Weichao and Renault, Tristan and Renga, Giorgia and Reue, Karen and Rewitz, Kim and Ribeiro De Andrade Ramos, Bruna and Riazuddin, S. Amer and Ribeiro-Rodrigues, Teresa M. and Ricci, Jean Ehrland and Ricci, Romeo and Riccio, Victoria and Richardson, Des R. and Rikihisa, Yasuko and Risbud, Makarand V. and Risueño, Ruth M. and Ritis, Konstantinos and Rizza, Salvatore and Rizzuto, Rosario and Roberts, Helen C. and Roberts, Luke D. and Robinson, Katherine J. and Roccheri, Maria Carmela and Rocchi, Stephane and Rodney, George G. and Rodrigues, Tiago and Rodrigues Silva, Vagner Ramon and Rodriguez, Amaia and Rodriguez-Barrueco, Ruth and Rodriguez-Henche, Nieves and Rodriguez-Rocha, Humberto and Roelofs, Jeroen and Rogers, Robert S. and Rogov, Vladimir V. and Rojo, Ana I. and Rolka, Krzysztof and Romanello, Vanina and Romani, Luigina and Romano, Alessandra and Romano, Patricia S. and Romeo-Guitart, David and Romero, Luis C. and Romero, Montserrat and Roney, Joseph C. and Rongo, Christopher and Roperto, Sante and Rosenfeldt, Mathias T. and Rosenstiel, Philip and Rosenwald, Anne G. and Roth, Kevin A. and Roth, Lynn and Roth, Steven and Rouschop, Kasper M.A. and Roussel, Benoit D. and Roux, Sophie and Rovere-Querini, Patrizia and Roy, Ajit and Rozieres, Aurore and Ruano, Diego and Rubinsztein, David C. and Rubtsova, Maria P. and Ruckdeschel, Klaus and Ruckenstuhl, Christoph and Rudolf, Emil and Rudolf, Rüdiger and Ruggieri, Alessandra and Ruparelia, Avnika Ashok and Rusmini, Paola and Russell, Ryan R. and Russo, Gian Luigi and Russo, Maria and Russo, Rossella and Ryabaya, Oxana O. and Ryan, Kevin M. and Ryu, Kwon Yul and Sabater-Arcis, Maria and Sachdev, Ulka and Sacher, Michael and Sachse, Carsten and Sadhu, Abhishek and Sadoshima, Junichi and Safren, Nathaniel and Saftig, Paul and Sagona, Antonia P. and Sahay, Gaurav and Sahebkar, Amirhossein and Sahin, Mustafa and Sahin, Ozgur and Sahni, Sumit and Saito, Nayuta and Saito, Shigeru and Saito, Tsunenori and Sakai, Ryohei and Sakai, Yasuyoshi and Sakamaki, Jun Ichi and Saksela, Kalle and Salazar, Gloria and Salazar-Degracia, Anna and Salekdeh, Ghasem H. and Saluja, Ashok K. and Sampaio-Marques, Belém and Sanchez, Maria Cecilia and Sanchez-Alcazar, Jose A. and Sanchez-Vera, Victoria and Sancho-Shimizu, Vanessa and Sanderson, J. Thomas and Sandri, Marco and Santaguida, Stefano and Santambrogio, Laura and Santana, Magda M. and Santoni, Giorgio and Sanz, Alberto and Sanz, Pascual and Saran, Shweta and Sardiello, Marco and Sargeant, Timothy J. and Sarin, Apurva and Sarkar, Chinmoy and Sarkar, Sovan and Sarrias, Maria Rosa and Sarkar, Surajit and Sarmah, Dipanka Tanu and Sarparanta, Jaakko and Sathyanarayan, Aishwarya and Sathyanarayanan, Ranganayaki and Scaglione, K. Matthew and Scatozza, Francesca and Schaefer, Liliana and Schafer, Zachary T. and Schaible, Ulrich E. and Schapira, Anthony H.V. and Scharl, Michael and Schatzl, Hermann M. and Schein, Catherine H. and Scheper, Wiep and Scheuring, David and Schiaffino, Maria Vittoria and Schiappacassi, Monica and Schindl, Rainer and Schlattner, Uwe and Schmidt, Oliver and Schmitt, Roland and Schmidt, Stephen D. and Schmitz, Ingo and Schmukler, Eran and Schneider, Anja and Schneider, Bianca E. and Schober, Romana and Schoijet, Alejandra C. and Schott, Micah B. and Schramm, Michael and Schröder, Bernd and Schuh, Kai and Schüller, Christoph and Schulze, Ryan J. and Schürmanns, Lea and Schwamborn, Jens C. and Schwarten, Melanie and Scialo, Filippo and Sciarretta, Sebastiano and Scott, Melanie J. and Scotto, Kathleen W. and Scovassi, A. 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M. and St. Clair, Daret and Stagni, Venturina and Staiano, Leopoldo and Stalnecker, Clint A. and Stankov, Metodi V. and Stathopulos, Peter B. and Stefan, Katja and Stefan, Sven Marcel and Stefanis, Leonidas and Steffan, Joan S. and Steinkasserer, Alexander and Stenmark, Harald and Sterneckert, Jared and Stevens, Craig and Stoka, Veronika and Storch, Stephan and Stork, Björn and Strappazzon, Flavie and Strohecker, Anne Marie and Stupack, Dwayne G. and Su, Huanxing and Su, Ling Yan and Su, Longxiang and Suarez-Fontes, Ana M. and Subauste, Carlos S. and Subbian, Selvakumar and Subirada, Paula V. and Sudhandiran, Ganapasam and Sue, Carolyn M. and Sui, Xinbing and Summers, Corey and Sun, Guangchao and Sun, Jun and Sun, Kang and Sun, Meng Xiang and Sun, Qiming and Sun, Yi and Sun, Zhongjie and Sunahara, Karen K.S. and Sundberg, Eva and Susztak, Katalin and Sutovsky, Peter and Suzuki, Hidekazu and Sweeney, Gary and Symons, J. 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P. and Thomas, Sufi Mary and Thomes, Paul G. and Thorburn, Andrew and Thukral, Lipi and Thum, Thomas and Thumm, Michael and Tian, Ling and Tichy, Ales and Till, Andreas and Timmerman, Vincent and Titorenko, Vladimir I. and Todi, Sokol V. and Todorova, Krassimira and Toivonen, Janne M. and Tomaipitinca, Luana and Tomar, Dhanendra and Tomas-Zapico, Cristina and Tomić, Sergej and Tong, Benjamin Chun Kit and Tong, Chao and Tong, Xin and Tooze, Sharon A. and Torgersen, Maria L. and Torii, Satoru and Torres-López, Liliana and Torriglia, Alicia and Towers, Christina G. and Towns, Roberto and Toyokuni, Shinya and Trajkovic, Vladimir and Tramontano, Donatella and Tran, Quynh Giao and Travassos, Leonardo H. and Trelford, Charles B. and Tremel, Shirley and Trougakos, Ioannis P. and Tsao, Betty P. and Tschan, Mario P. and Tse, Hung Fat and Tse, Tak Fu and Tsugawa, Hitoshi and Tsvetkov, Andrey S. and Tumbarello, David A. and Tumtas, Yasin and Tuñón, María J. and Turcotte, Sandra and Turk, Boris and Turk, Vito and Turner, Bradley J. and Tuxworth, Richard I. and Tyler, Jessica K. and Tyutereva, Elena V. and Uchiyama, Yasuo and Ugun-Klusek, Aslihan and Uhlig, Holm H. and Ułamek-Kozioł, Marzena and Ulasov, Ilya V. and Umekawa, Midori and Ungermann, Christian and Unno, Rei and Urbe, Sylvie and Uribe-Carretero, Elisabet and Üstün, Suayib and Uversky, Vladimir N. and Vaccari, Thomas and Vaccaro, Maria I. and Vahsen, Björn F. and Vakifahmetoglu-Norberg, Helin and Valdor, Rut and Valente, Maria J. and Valko, Ayelén and Vallee, Richard B. and Valverde, Angela M. and Van Den Berghe, Greet and Van Der Veen, Stijn and Van Kaer, Luc and Van Loosdregt, Jorg and Van Wijk, Sjoerd J.L. and Vandenberghe, Wim and Vanhorebeek, Ilse and Vannier-Santos, Marcos A. and Vannini, Nicola and Vanrell, M. Cristina and Vantaggiato, Chiara and Varano, Gabriele and Varela-Nieto, Isabel and Varga, Máté and Vasconcelos, M. Helena and Vats, Somya and Vavvas, Demetrios G. and Vega-Naredo, Ignacio and Vega-Rubin-De-Celis, Silvia and Velasco, Guillermo and Velázquez, Ariadna P. and Vellai, Tibor and Vellenga, Edo and Velotti, Francesca and Verdier, Mireille and Verginis, Panayotis and Vergne, Isabelle and Verkade, Paul and Verma, Manish and Verstreken, Patrik and Vervliet, Tim and Vervoorts, Jörg and Vessoni, Alexandre T. and Victor, Victor M. and Vidal, Michel and Vidoni, Chiara and Vieira, Otilia V. and Vierstra, Richard D. and Viganó, Sonia and Vihinen, Helena and Vijayan, Vinoy and Vila, Miquel and Vilar, Marçal and Villalba, José M. and Villalobo, Antonio and Villarejo-Zori, Beatriz and Villarroya, Francesc and Villarroya, Joan and Vincent, Olivier and Vindis, Cecile and Viret, Christophe and Viscomi, Maria Teresa and Visnjic, Dora and Vitale, Ilio and Vocadlo, David J. and Voitsekhovskaja, Olga V. and Volonté, Cinzia and Volta, Mattia and Vomero, Marta and Von Haefen, Clarissa and Vooijs, Marc A. and Voos, Wolfgang and Vucicevic, Ljubica and Wade-Martins, Richard and Waguri, Satoshi and Waite, Kenrick A. and Wakatsuki, Shuji and Walker, David W. and Walker, Mark J. and Walker, Simon A. and Walter, Jochen and Wandosell, Francisco G. and Wang, Bo and Wang, Chao Yung and Wang, Chen and Wang, Chenran and Wang, Chenwei and Wang, Cun Yu and Wang, Dong and Wang, Fangyang and Wang, Feng and Wang, Fengming and Wang, Guansong and Wang, Han and Wang, Hao and Wang, Hexiang and Wang, Hong Gang and Wang, Jianrong and Wang, Jigang and Wang, Jiou and Wang, Jundong and Wang, Kui and Wang, Lianrong and Wang, Liming and Wang, Maggie Haitian and Wang, Meiqing and Wang, Nanbu and Wang, Pengwei and Wang, Peipei and Wang, Ping and Wang, Ping and Wang, Qing Jun and Wang, Qing and Wang, Qing Kenneth and Wang, Qiong A. and Wang, Wen Tao and Wang, Wuyang and Wang, Xinnan and Wang, Xuejun and Wang, Yan and Wang, Yanchang and Wang, Yanzhuang and Wang, Yen Yun and Wang, Yihua and Wang, Yipeng and Wang, Yu and Wang, Yuqi and Wang, Zhe and Wang, Zhenyu and Wang, Zhouguang and Warnes, Gary and Warnsmann, Verena and Watada, Hirotaka and Watanabe, Eizo and Watchon, Maxinne and Wawrzyńska, Anna and Weaver, Timothy E. and Wegrzyn, Grzegorz and Wehman, Ann M. and Wei, Huafeng and Wei, Lei and Wei, Taotao and Wei, Yongjie and Weiergräber, Oliver H. and Weihl, Conrad C. and Weindl, Günther and Weiskirchen, Ralf and Wells, Alan and Wen, Runxia H. and Wen, Xin and Werner, Antonia and Weykopf, Beatrice and Wheatley, Sally P. and Whitton, J. Lindsay and Whitworth, Alexander J. and Wiktorska, Katarzyna and Wildenberg, Manon E. and Wileman, Tom and Wilkinson, Simon and Willbold, Dieter and Williams, Brett and Williams, Robin S.B. and Williams, Roger L. and Williamson, Peter R. and Wilson, Richard A. and Winner, Beate and Winsor, Nathaniel J. and Witkin, Steven S. and Wodrich, Harald and Woehlbier, Ute and Wollert, Thomas and Wong, Esther and Wong, Jack Ho and Wong, Richard W. and Wong, Vincent Kam Wai and Wong, W. Wei Lynn and Wu, An Guo and Wu, Chengbiao and Wu, Jian and Wu, Junfang and Wu, Kenneth K. and Wu, Min and Wu, Shan Ying and Wu, Shengzhou and Wu, Shu Yan and Wu, Shufang and Wu, William K.K. and Wu, Xiaohong and Wu, Xiaoqing and Wu, Yao Wen and Wu, Yihua and Xavier, Ramnik J. and Xia, Hongguang and Xia, Lixin and Xia, Zhengyuan and Xiang, Ge and Xiang, Jin and Xiang, Mingliang and Xiang, Wei and Xiao, Bin and Xiao, Guozhi and Xiao, Hengyi and Xiao, Hong Tao and Xiao, Jian and Xiao, Lan and Xiao, Shi and Xiao, Yin and Xie, Baoming and Xie, Chuan Ming and Xie, Min and Xie, Yuxiang and Xie, Zhiping and Xie, Zhonglin and Xilouri, Maria and Xu, Congfeng and Xu, En and Xu, Haoxing and Xu, Jing and Xu, Jin Rong and Xu, Liang and Xu, Wen Wen and Xu, Xiulong and Xue, Yu and Yakhine-Diop, Sokhna M.S. and Yamaguchi, Masamitsu and Yamaguchi, Osamu and Yamamoto, Ai and Yamashina, Shunhei and Yan, Shengmin and Yan, Shian Jang and Yan, Zhen and Yanagi, Yasuo and Yang, Chuanbin and Yang, Dun Sheng and Yang, Huan and Yang, Huang Tian and Yang, Hui and Yang, Jin Ming and Yang, Jing and Yang, Jingyu and Yang, Ling and Yang, Liu and Yang, Ming and Yang, Pei Ming and Yang, Qian and Yang, Seungwon and Yang, Shu and Yang, Shun Fa and Yang, Wannian and Yang, Wei Yuan and Yang, Xiaoyong and Yang, Xuesong and Yang, Yi and Yang, Ying and Yao, Honghong and Yao, Shenggen and Yao, Xiaoqiang and Yao, Yong Gang and Yao, Yong Ming and Yasui, Takahiro and Yazdankhah, Meysam and Yen, Paul M. and Yi, Cong and Yin, Xiao Ming and Yin, Yanhai and Yin, Zhangyuan and Yin, Ziyi and Ying, Meidan and Ying, Zheng and Yip, Calvin K. and Yiu, Stephanie Pei Tung and Yoo, Young H. and Yoshida, Kiyotsugu and Yoshii, Saori R. and Yoshimori, Tamotsu and Yousefi, Bahman and Yu, Boxuan and Yu, Haiyang and Yu, Jun and Yu, Jun and Yu, Li and Yu, Ming Lung and Yu, Seong Woon and Yu, Victor C. and Yu, W. Haung and Yu, Zhengping and Yu, Zhou and Yuan, Junying and Yuan, Ling Qing and Yuan, Shilin and Yuan, Shyng Shiou F. and Yuan, Yanggang and Yuan, Zengqiang and Yue, Jianbo and Yue, Zhenyu and Yun, Jeanho and Yung, Raymond L. and Zacks, David N. and Zaffagnini, Gabriele and Zambelli, Vanessa O. and Zanella, Isabella and Zang, Qun S. and Zanivan, Sara and Zappavigna, Silvia and Zaragoza, Pilar and Zarbalis, Konstantinos S. and Zarebkohan, Amir and Zarrouk, Amira and Zeitlin, Scott O. and Zeng, Jialiu and Zeng, Ju Deng and Žerovnik, Eva and Zhan, Lixuan and Zhang, Bin and Zhang, Donna D. and Zhang, Hanlin and Zhang, Hong and Zhang, Hong and Zhang, Honghe and Zhang, Huafeng and Zhang, Huaye and Zhang, Hui and Zhang, Hui Ling and Zhang, Jianbin and Zhang, Jianhua and Zhang, Jing Pu and Zhang, Kalin Y.B. and Zhang, Leshuai W. and Zhang, Lin and Zhang, Lisheng and Zhang, Lu and Zhang, Luoying and Zhang, Menghuan and Zhang, Peng and Zhang, Sheng and Zhang, Wei and Zhang, Xiangnan and Zhang, Xiao Wei and Zhang, Xiaolei and Zhang, Xiaoyan and Zhang, Xin and Zhang, Xinxin and Zhang, Xu Dong and Zhang, Yang and Zhang, Yanjin and Zhang, Yi and Zhang, Ying Dong and Zhang, Yingmei and Zhang, Yuan Yuan and Zhang, Yuchen and Zhang, Zhe and Zhang, Zhengguang and Zhang, Zhibing and Zhang, Zhihai and Zhang, Zhiyong and Zhang, Zili and Zhao, Haobin and Zhao, Lei and Zhao, Shuang and Zhao, Tongbiao and Zhao, Xiao Fan and Zhao, Ying and Zhao, Yongchao and Zhao, Yongliang and Zhao, Yuting and Zheng, Guoping and Zheng, Kai and Zheng, Ling and Zheng, Shizhong and Zheng, Xi Long and Zheng, Yi and Zheng, Zu Guo and Zhivotovsky, Boris and Zhong, Qing and Zhou, Ao and Zhou, Ben and Zhou, Cefan and Zhou, Gang and Zhou, Hao and Zhou, Hong and Zhou, Hongbo and Zhou, Jie and Zhou, Jing and Zhou, Jing and Zhou, Jiyong and Zhou, Kailiang and Zhou, Rongjia and Zhou, Xu Jie and Zhou, Yanshuang and Zhou, Yinghong and Zhou, Yubin and Zhou, Zheng Yu and Zhou, Zhou and Zhu, Binglin and Zhu, Changlian and Zhu, Guo Qing and Zhu, Haining and Zhu, Hongxin and Zhu, Hua and Zhu, Wei Guo and Zhu, Yanping and Zhu, Yushan and Zhuang, Haixia and Zhuang, Xiaohong and Zientara-Rytter, Katarzyna and Zimmermann, Christine M. and Ziviani, Elena and Zoladek, Teresa and Zong, Wei Xing and Zorov, Dmitry B. and Zorzano, Antonio and Zou, Weiping and Zou, Zhen and Zou, Zhengzhi and Zuryn, Steven and Zwerschke, Werner and Brand-Saberi, Beate and Dong, X. Charlie and Kenchappa, Chandra Shekar and Li, Zuguo and Lin, Yong and Oshima, Shigeru and Rong, Yueguang and Sluimer, Judith C. and Stallings, Christina L. and Tong, Chun Kit}, issn = {1554-8635}, journal = {Autophagy}, number = {1}, pages = {1--382}, publisher = {Taylor & Francis}, title = {{Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)}}, doi = {10.1080/15548627.2020.1797280}, volume = {17}, year = {2021}, } @article{9379, abstract = {When B cells encounter membrane-bound antigens, the formation and coalescence of B cell antigen receptor (BCR) microclusters amplifies BCR signaling. The ability of B cells to probe the surface of antigen-presenting cells (APCs) and respond to APC-bound antigens requires remodeling of the actin cytoskeleton. Initial BCR signaling stimulates actin-related protein (Arp) 2/3 complex-dependent actin polymerization, which drives B cell spreading as well as the centripetal movement and coalescence of BCR microclusters at the B cell-APC synapse. Sustained actin polymerization depends on concomitant actin filament depolymerization, which enables the recycling of actin monomers and Arp2/3 complexes. Cofilin-mediated severing of actin filaments is a rate-limiting step in the morphological changes that occur during immune synapse formation. Hence, regulators of cofilin activity such as WD repeat-containing protein 1 (Wdr1), LIM domain kinase (LIMK), and coactosin-like 1 (Cotl1) may also be essential for actin-dependent processes in B cells. Wdr1 enhances cofilin-mediated actin disassembly. Conversely, Cotl1 competes with cofilin for binding to actin and LIMK phosphorylates cofilin and prevents it from binding to actin filaments. We now show that Wdr1 and LIMK have distinct roles in BCR-induced assembly of the peripheral actin structures that drive B cell spreading, and that cofilin, Wdr1, and LIMK all contribute to the actin-dependent amplification of BCR signaling at the immune synapse. Depleting Cotl1 had no effect on these processes. Thus, the Wdr1-LIMK-cofilin axis is critical for BCR-induced actin remodeling and for B cell responses to APC-bound antigens.}, author = {Bolger-Munro, Madison and Choi, Kate and Cheung, Faith and Liu, Yi Tian and Dang-Lawson, May and Deretic, Nikola and Keane, Connor and Gold, Michael R.}, issn = {2296-634X}, journal = {Frontiers in Cell and Developmental Biology}, keywords = {B cell, actin, immune synapse, cell spreading, cofilin, WDR1 (AIP1), LIM domain kinase, B cell receptor (BCR)}, publisher = {Frontiers Media}, title = {{The Wdr1-LIMK-Cofilin axis controls B cell antigen receptor-induced actin remodeling and signaling at the immune synapse}}, doi = {10.3389/fcell.2021.649433}, volume = {9}, year = {2021}, } @phdthesis{9623, abstract = {Cytoplasmic reorganizations are essential for morphogenesis. In large cells like oocytes, these reorganizations become crucial in patterning the oocyte for later stages of embryonic development. Ascidians oocytes reorganize their cytoplasm (ooplasm) in a spectacular manner. Ooplasmic reorganization is initiated at fertilization with the contraction of the actomyosin cortex along the animal-vegetal axis of the oocyte, driving the accumulation of cortical endoplasmic reticulum (cER), maternal mRNAs associated to it and a mitochondria-rich subcortical layer – the myoplasm – in a region of the vegetal pole termed contraction pole (CP). Here we have used the species Phallusia mammillata to investigate the changes in cell shape that accompany these reorganizations and the mechanochemical mechanisms underlining CP formation. We report that the length of the animal-vegetal (AV) axis oscillates upon fertilization: it first undergoes a cycle of fast elongation-lengthening followed by a slow expansion of mainly the vegetal pole (VP) of the cell. We show that the fast oscillation corresponds to a dynamic polarization of the actin cortex as a result of a fertilization-induced increase in cortical tension in the oocyte that triggers a rupture of the cortex at the animal pole and the establishment of vegetal-directed cortical flows. These flows are responsible for the vegetal accumulation of actin causing the VP to flatten. We find that the slow expansion of the VP, leading to CP formation, correlates with a relaxation of the vegetal cortex and that the myoplasm plays a role in the expansion. We show that the myoplasm is a solid-like layer that buckles under compression forces arising from the contracting actin cortex at the VP. Straightening of the myoplasm when actin flows stops, facilitates the expansion of the VP and the CP. Altogether, our results present a previously unrecognized role for the myoplasm in ascidian ooplasmic segregation. }, author = {Caballero Mancebo, Silvia}, isbn = {978-3-99078-012-1}, issn = {2663-337X}, pages = {111}, publisher = {Institute of Science and Technology Austria}, title = {{Fertilization-induced deformations are controlled by the actin cortex and a mitochondria-rich subcortical layer in ascidian oocytes}}, doi = {10.15479/at:ista:9623}, year = {2021}, } @article{9006, abstract = {Cytoplasm is a gel-like crowded environment composed of various macromolecules, organelles, cytoskeletal networks, and cytosol. The structure of the cytoplasm is highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules are restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the crowded nature of the cytoplasm at the microscopic scale, large-scale reorganization of the cytoplasm is essential for important cellular functions, such as cell division and polarization. How such mesoscale reorganization of the cytoplasm is achieved, especially for large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, is only beginning to be understood. In this review, we will discuss recent advances in elucidating the molecular, cellular, and biophysical mechanisms by which the cytoskeleton drives cytoplasmic reorganization across different scales, structures, and species.}, author = {Shamipour, Shayan and Caballero Mancebo, Silvia and Heisenberg, Carl-Philipp J}, issn = {18781551}, journal = {Developmental Cell}, number = {2}, pages = {P213--226}, publisher = {Elsevier}, title = {{Cytoplasm's got moves}}, doi = {10.1016/j.devcel.2020.12.002}, volume = {56}, year = {2021}, } @phdthesis{9397, abstract = {Accumulation of interstitial fluid (IF) between embryonic cells is a common phenomenon in vertebrate embryogenesis. Unlike other model systems, where these accumulations coalesce into a large central cavity – the blastocoel, in zebrafish, IF is more uniformly distributed between the deep cells (DC) before the onset of gastrulation. This is likely due to the presence of a large extraembryonic structure – the yolk cell (YC) at the position where the blastocoel typically forms in other model organisms. IF has long been speculated to play a role in tissue morphogenesis during embryogenesis, but direct evidence supporting such function is still sparse. Here we show that the relocalization of IF to the interface between the YC and DC/epiblast is critical for axial mesendoderm (ME) cell protrusion formation and migration along this interface, a key process in embryonic axis formation. We further demonstrate that axial ME cell migration and IF relocalization engage in a positive feedback loop, where axial ME migration triggers IF accumulation ahead of the advancing axial ME tissue by mechanically compressing the overlying epiblast cell layer. Upon compression, locally induced flow relocalizes the IF through the porous epiblast tissue resulting in an IF accumulation ahead of the leading axial ME. This IF accumulation, in turn, promotes cell protrusion formation and migration of the leading axial ME cells, thereby facilitating axial ME extension. Our findings reveal a central role of dynamic IF relocalization in orchestrating germ layer morphogenesis during gastrulation.}, author = {Huljev, Karla}, issn = {2663-337X}, pages = {101}, publisher = {Institute of Science and Technology Austria}, title = {{Coordinated spatiotemporal reorganization of interstitial fluid is required for axial mesendoderm migration in zebrafish gastrulation}}, doi = {10.15479/at:ista:9397}, year = {2021}, } @article{7888, abstract = {Embryonic stem cell cultures are thought to self-organize into embryoid bodies, able to undergo symmetry-breaking, germ layer specification and even morphogenesis. Yet, it is unclear how to reconcile this remarkable self-organization capacity with classical experiments demonstrating key roles for extrinsic biases by maternal factors and/or extraembryonic tissues in embryogenesis. Here, we show that zebrafish embryonic tissue explants, prepared prior to germ layer induction and lacking extraembryonic tissues, can specify all germ layers and form a seemingly complete mesendoderm anlage. Importantly, explant organization requires polarized inheritance of maternal factors from dorsal-marginal regions of the blastoderm. Moreover, induction of endoderm and head-mesoderm, which require peak Nodal-signaling levels, is highly variable in explants, reminiscent of embryos with reduced Nodal signals from the extraembryonic tissues. Together, these data suggest that zebrafish explants do not undergo bona fide self-organization, but rather display features of genetically encoded self-assembly, where intrinsic genetic programs control the emergence of order.}, author = {Schauer, Alexandra and Nunes Pinheiro, Diana C and Hauschild, Robert and Heisenberg, Carl-Philipp J}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Zebrafish embryonic explants undergo genetically encoded self-assembly}}, doi = {10.7554/elife.55190}, volume = {9}, year = {2020}, } @article{8680, abstract = {Animal development entails the organization of specific cell types in space and time, and spatial patterns must form in a robust manner. In the zebrafish spinal cord, neural progenitors form stereotypic patterns despite noisy morphogen signaling and large-scale cellular rearrangements during morphogenesis and growth. By directly measuring adhesion forces and preferences for three types of endogenous neural progenitors, we provide evidence for the differential adhesion model in which differences in intercellular adhesion mediate cell sorting. Cell type–specific combinatorial expression of different classes of cadherins (N-cadherin, cadherin 11, and protocadherin 19) results in homotypic preference ex vivo and patterning robustness in vivo. Furthermore, the differential adhesion code is regulated by the sonic hedgehog morphogen gradient. We propose that robust patterning during tissue morphogenesis results from interplay between adhesion-based self-organization and morphogen-directed patterning.}, author = {Tsai, Tony Y.-C. and Sikora, Mateusz K and Xia, Peng and Colak-Champollion, Tugba and Knaut, Holger and Heisenberg, Carl-Philipp J and Megason, Sean G.}, issn = {1095-9203}, journal = {Science}, keywords = {Multidisciplinary}, number = {6512}, pages = {113--116}, publisher = {American Association for the Advancement of Science}, title = {{An adhesion code ensures robust pattern formation during tissue morphogenesis}}, doi = {10.1126/science.aba6637}, volume = {370}, year = {2020}, } @article{8957, abstract = {Global tissue tension anisotropy has been shown to trigger stereotypical cell division orientation by elongating mitotic cells along the main tension axis. Yet, how tissue tension elongates mitotic cells despite those cells undergoing mitotic rounding (MR) by globally upregulating cortical actomyosin tension remains unclear. We addressed this question by taking advantage of ascidian embryos, consisting of a small number of interphasic and mitotic blastomeres and displaying an invariant division pattern. We found that blastomeres undergo MR by locally relaxing cortical tension at their apex, thereby allowing extrinsic pulling forces from neighboring interphasic blastomeres to polarize their shape and thus division orientation. Consistently, interfering with extrinsic forces by reducing the contractility of interphasic blastomeres or disrupting the establishment of asynchronous mitotic domains leads to aberrant mitotic cell division orientations. Thus, apical relaxation during MR constitutes a key mechanism by which tissue tension anisotropy controls stereotypical cell division orientation.}, author = {Godard, Benoit G and Dumollard, Rémi and Munro, Edwin and Chenevert, Janet and Hebras, Céline and Mcdougall, Alex and Heisenberg, Carl-Philipp J}, issn = {18781551}, journal = {Developmental Cell}, number = {6}, pages = {695--706}, publisher = {Elsevier}, title = {{Apical relaxation during mitotic rounding promotes tension-oriented cell division}}, doi = {10.1016/j.devcel.2020.10.016}, volume = {55}, year = {2020}, } @inbook{7227, abstract = {Gastrulation entails specification and formation of three embryonic germ layers—ectoderm, mesoderm and endoderm—thereby establishing the basis for the future body plan. In zebrafish embryos, germ layer specification occurs during blastula and early gastrula stages (Ho & Kimmel, 1993), a period when the main morphogenetic movements underlying gastrulation are initiated. Hence, the signals driving progenitor cell fate specification, such as Nodal ligands from the TGF-β family, also play key roles in regulating germ layer progenitor cell segregation (Carmany-Rampey & Schier, 2001; David & Rosa, 2001; Feldman et al., 2000; Gritsman et al., 1999; Keller et al., 2008). In this review, we summarize and discuss the main signaling pathways involved in germ layer progenitor cell fate specification and segregation, specifically focusing on recent advances in understanding the interplay between mesoderm and endoderm specification and the internalization movements at the onset of zebrafish gastrulation.}, author = {Nunes Pinheiro, Diana C and Heisenberg, Carl-Philipp J}, booktitle = {Gastrulation: From Embryonic Pattern to Form}, issn = {00702153}, pages = {343--375}, publisher = {Elsevier}, title = {{Zebrafish gastrulation: Putting fate in motion}}, doi = {10.1016/bs.ctdb.2019.10.009}, volume = {136}, year = {2020}, } @inbook{7410, abstract = {Epiboly is a conserved gastrulation movement describing the thinning and spreading of a sheet or multi-layer of cells. The zebrafish embryo has emerged as a vital model system to address the cellular and molecular mechanisms that drive epiboly. In the zebrafish embryo, the blastoderm, consisting of a simple squamous epithelium (the enveloping layer) and an underlying mass of deep cells, as well as a yolk nuclear syncytium (the yolk syncytial layer) undergo epiboly to internalize the yolk cell during gastrulation. The major events during zebrafish epiboly are: expansion of the enveloping layer and the internal yolk syncytial layer, reduction and removal of the yolk membrane ahead of the advancing blastoderm margin and deep cell rearrangements between the enveloping layer and yolk syncytial layer to thin the blastoderm. Here, work addressing the cellular and molecular mechanisms as well as the sources of the mechanical forces that underlie these events is reviewed. The contribution of recent findings to the current model of epiboly as well as open questions and future prospects are also discussed.}, author = {Bruce, Ashley E.E. and Heisenberg, Carl-Philipp J}, booktitle = {Gastrulation: From Embryonic Pattern to Form}, editor = {Solnica-Krezel, Lilianna }, isbn = {9780128127988}, issn = {0070-2153}, pages = {319--341}, publisher = {Elsevier}, title = {{Mechanisms of zebrafish epiboly: A current view}}, doi = {10.1016/bs.ctdb.2019.07.001}, volume = {136}, year = {2020}, } @unpublished{9750, abstract = {Tension of the actomyosin cell cortex plays a key role in determining cell-cell contact growth and size. The level of cortical tension outside of the cell-cell contact, when pulling at the contact edge, scales with the total size to which a cell-cell contact can grow1,2. Here we show in zebrafish primary germ layer progenitor cells that this monotonic relationship only applies to a narrow range of cortical tension increase, and that above a critical threshold, contact size inversely scales with cortical tension. This switch from cortical tension increasing to decreasing progenitor cell-cell contact size is caused by cortical tension promoting E-cadherin anchoring to the actomyosin cytoskeleton, thereby increasing clustering and stability of E-cadherin at the contact. Once tension-mediated E-cadherin stabilization at the contact exceeds a critical threshold level, the rate by which the contact expands in response to pulling forces from the cortex sharply drops, leading to smaller contacts at physiologically relevant timescales of contact formation. Thus, the activity of cortical tension in expanding cell-cell contact size is limited by tension stabilizing E-cadherin-actin complexes at the contact.}, author = {Slovakova, Jana and Sikora, Mateusz K and Caballero Mancebo, Silvia and Krens, Gabriel and Kaufmann, Walter and Huljev, Karla and Heisenberg, Carl-Philipp J}, booktitle = {bioRxiv}, pages = {41}, publisher = {Cold Spring Harbor Laboratory}, title = {{Tension-dependent stabilization of E-cadherin limits cell-cell contact expansion}}, doi = {10.1101/2020.11.20.391284}, year = {2020}, } @phdthesis{8350, abstract = {Cytoplasm is a gel-like crowded environment composed of tens of thousands of macromolecules, organelles, cytoskeletal networks and cytosol. The structure of the cytoplasm is thought to be highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules is very restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the jammed nature of the cytoplasm at the microscopic scale, large-scale reorganization of cytoplasm is essential for important cellular functions, such as nuclear positioning and cell division. How such mesoscale reorganization of the cytoplasm is achieved, especially for very large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, has only begun to be understood. In this thesis, I focus on the recent advances in elucidating the molecular, cellular and biophysical principles underlying cytoplasmic organization across different scales, structures and species. First, I outline which of these principles have been identified by reductionist approaches, such as in vitro reconstitution assays, where boundary conditions and components can be modulated at ease. I then describe how the theoretical and experimental framework established in these reduced systems have been applied to their more complex in vivo counterparts, in particular oocytes and embryonic syncytial structures, and discuss how such complex biological systems can initiate symmetry breaking and establish patterning. Specifically, I examine an example of large-scale reorganizations taking place in zebrafish embryos, where extensive cytoplasmic streaming leads to the segregation of cytoplasm from yolk granules along the animal-vegetal axis of the embryo. Using biophysical experimentation and theory, I investigate the forces underlying this process, to show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the embryo. This wave functions in segregation by both pulling cytoplasm animally and pushing yolk granules vegetally. Cytoplasm pulling is mediated by bulk actin network flows exerting friction forces on the cytoplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. This study defines a novel role of bulk actin polymerization waves in embryo polarization via cytoplasmic segregation. Lastly, I describe the cytoplasmic reorganizations taking place during zebrafish oocyte maturation, where the initial segregation of the cytoplasm and yolk granules occurs. Here, I demonstrate a previously uncharacterized wave of microtubule aster formation, traveling the oocyte along the animal-vegetal axis. Further research is required to determine the role of such microtubule structures in cytoplasmic reorganizations therein. Collectively, these studies provide further evidence for the coupling between cell cytoskeleton and cell cycle machinery, which can underlie a core self-organizing mechanism for orchestrating large-scale reorganizations in a cell-cycle-tunable manner, where the modulations of the force-generating machinery and cytoplasmic mechanics can be harbored to fulfill cellular functions.}, author = {Shamipour, Shayan}, issn = {2663-337X}, pages = {107}, publisher = {Institute of Science and Technology Austria}, title = {{Bulk actin dynamics drive phase segregation in zebrafish oocytes }}, doi = {10.15479/AT:ISTA:8350}, year = {2020}, } @inbook{5793, abstract = {The transcription coactivator, Yes-associated protein (YAP), which is a nuclear effector of the Hippo signaling pathway, has been shown to be a mechano-transducer. By using mutant fish and human 3D spheroids, we have recently demonstrated that YAP is also a mechano-effector. YAP functions in three-dimensional (3D) morphogenesis of organ and global body shape by controlling actomyosin-mediated tissue tension. In this chapter, we present a platform that links the findings in fish embryos with human cells. The protocols for analyzing tissue tension-mediated global body shape/organ morphogenesis in vivo and ex vivo using medaka fish embryos and in vitro using human cell spheroids represent useful tools for unraveling the molecular mechanisms by which YAP functions in regulating global body/organ morphogenesis.}, author = {Asaoka, Yoichi and Morita, Hitoshi and Furumoto, Hiroko and Heisenberg, Carl-Philipp J and Furutani-Seiki, Makoto}, booktitle = {The hippo pathway}, editor = {Hergovich, Alexander}, isbn = {978-1-4939-8909-6}, pages = {167--181}, publisher = {Springer}, title = {{Studying YAP-mediated 3D morphogenesis using fish embryos and human spheroids}}, doi = {10.1007/978-1-4939-8910-2_14}, volume = {1893}, year = {2019}, } @article{6025, abstract = {Non-canonical Wnt signaling plays a central role for coordinated cell polarization and directed migration in metazoan development. While spatiotemporally restricted activation of non-canonical Wnt-signaling drives cell polarization in epithelial tissues, it remains unclear whether such instructive activity is also critical for directed mesenchymal cell migration. Here, we developed a light-activated version of the non-canonical Wnt receptor Frizzled 7 (Fz7) to analyze how restricted activation of non-canonical Wnt signaling affects directed anterior axial mesendoderm (prechordal plate, ppl) cell migration within the zebrafish gastrula. We found that Fz7 signaling is required for ppl cell protrusion formation and migration and that spatiotemporally restricted ectopic activation is capable of redirecting their migration. Finally, we show that uniform activation of Fz7 signaling in ppl cells fully rescues defective directed cell migration in fz7 mutant embryos. Together, our findings reveal that in contrast to the situation in epithelial cells, non-canonical Wnt signaling functions permissively rather than instructively in directed mesenchymal cell migration during gastrulation.}, author = {Capek, Daniel and Smutny, Michael and Tichy, Alexandra Madelaine and Morri, Maurizio and Janovjak, Harald L and Heisenberg, Carl-Philipp J}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Light-activated Frizzled7 reveals a permissive role of non-canonical wnt signaling in mesendoderm cell migration}}, doi = {10.7554/eLife.42093}, volume = {8}, year = {2019}, } @article{6087, abstract = {Cell fate specification by lateral inhibition typically involves contact signaling through the Delta-Notch signaling pathway. However, whether this is the only signaling mode mediating lateral inhibition remains unclear. Here we show that in zebrafish oogenesis, a group of cells within the granulosa cell layer at the oocyte animal pole acquire elevated levels of the transcriptional coactivator TAZ in their nuclei. One of these cells, the future micropyle precursor cell (MPC), accumulates increasingly high levels of nuclear TAZ and grows faster than its surrounding cells, mechanically compressing those cells, which ultimately lose TAZ from their nuclei. Strikingly, relieving neighbor-cell compression by MPC ablation or aspiration restores nuclear TAZ accumulation in neighboring cells, eventually leading to MPC re-specification from these cells. Conversely, MPC specification is defective in taz−/− follicles. These findings uncover a novel mode of lateral inhibition in cell fate specification based on mechanical signals controlling TAZ activity.}, author = {Xia, Peng and Gütl, Daniel J and Zheden, Vanessa and Heisenberg, Carl-Philipp J}, journal = {Cell}, number = {6}, pages = {1379--1392.e14}, publisher = {Elsevier}, title = {{Lateral inhibition in cell specification mediated by mechanical signals modulating TAZ activity}}, doi = {10.1016/j.cell.2019.01.019}, volume = {176}, year = {2019}, } @article{6601, abstract = {There is increasing evidence that both mechanical and biochemical signals play important roles in development and disease. The development of complex organisms, in particular, has been proposed to rely on the feedback between mechanical and biochemical patterning events. This feedback occurs at the molecular level via mechanosensation but can also arise as an emergent property of the system at the cellular and tissue level. In recent years, dynamic changes in tissue geometry, flow, rheology, and cell fate specification have emerged as key platforms of mechanochemical feedback loops in multiple processes. Here, we review recent experimental and theoretical advances in understanding how these feedbacks function in development and disease.}, author = {Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {00928674}, journal = {Cell}, number = {1}, pages = {12--25}, publisher = {Elsevier}, title = {{Mechanochemical feedback loops in development and disease}}, doi = {10.1016/j.cell.2019.05.052}, volume = {178}, year = {2019}, } @article{6631, abstract = {The spatiotemporal organization of cell divisions constitutes an integral part in the development of multicellular organisms, and mis-regulation of cell divisions can lead to severe developmental defects. Cell divisions have an important morphogenetic function in development by regulating growth and shape acquisition of developing tissues, and, conversely, tissue morphogenesis is known to affect both the rate and orientation of cell divisions. Moreover, cell divisions are associated with an extensive reorganization of the cytoskeleton and adhesion apparatus in the dividing cells that in turn can affect large-scale tissue rheological properties. Thus, the interplay between cell divisions and tissue morphogenesis plays a key role in embryo and tissue morphogenesis.}, author = {Godard, Benoit G and Heisenberg, Carl-Philipp J}, issn = {0955-0674}, journal = {Current Opinion in Cell Biology}, pages = {114--120}, publisher = {Elsevier}, title = {{Cell division and tissue mechanics}}, doi = {10.1016/j.ceb.2019.05.007}, volume = {60}, year = {2019}, } @article{6837, abstract = {Migrasomes are a recently discovered type of extracellular vesicles that are characteristically generated along retraction fibers in migrating cells. Two studies now show how migrasomes are formed and how they function in the physiologically relevant context of the developing zebrafish embryo.}, author = {Tavano, Ste and Heisenberg, Carl-Philipp J}, issn = {1476-4679}, journal = {Nature Cell Biology}, number = {8}, pages = {918--920}, publisher = {Springer Nature}, title = {{Migrasomes take center stage}}, doi = {10.1038/s41556-019-0369-3}, volume = {21}, year = {2019}, } @article{6899, abstract = {Intra-organ communication guides morphogenetic processes that are essential for an organ to carry out complex physiological functions. In the heart, the growth of the myocardium is tightly coupled to that of the endocardium, a specialized endothelial tissue that lines its interior. Several molecular pathways have been implicated in the communication between these tissues including secreted factors, components of the extracellular matrix, or proteins involved in cell-cell communication. Yet, it is unknown how the growth of the endocardium is coordinated with that of the myocardium. Here, we show that an increased expansion of the myocardial atrial chamber volume generates higher junctional forces within endocardial cells. This leads to biomechanical signaling involving VE-cadherin, triggering nuclear localization of the Hippo pathway transcriptional regulator Yap1 and endocardial proliferation. Our work suggests that the growth of the endocardium results from myocardial chamber volume expansion and ends when the tension on the tissue is relaxed.}, author = {Bornhorst, Dorothee and Xia, Peng and Nakajima, Hiroyuki and Dingare, Chaitanya and Herzog, Wiebke and Lecaudey, Virginie and Mochizuki, Naoki and Heisenberg, Carl-Philipp J and Yelon, Deborah and Abdelilah-Seyfried, Salim}, issn = {20411723}, journal = {Nature communications}, number = {1}, pages = {4113}, publisher = {Nature Publishing Group}, title = {{Biomechanical signaling within the developing zebrafish heart attunes endocardial growth to myocardial chamber dimensions}}, doi = {10.1038/s41467-019-12068-x}, volume = {10}, year = {2019}, } @article{6980, abstract = {Tissue morphogenesis in multicellular organisms is brought about by spatiotemporal coordination of mechanical and chemical signals. Extensive work on how mechanical forces together with the well‐established morphogen signalling pathways can actively shape living tissues has revealed evolutionary conserved mechanochemical features of embryonic development. More recently, attention has been drawn to the description of tissue material properties and how they can influence certain morphogenetic processes. Interestingly, besides the role of tissue material properties in determining how much tissues deform in response to force application, there is increasing theoretical and experimental evidence, suggesting that tissue material properties can abruptly and drastically change in development. These changes resemble phase transitions, pointing at the intriguing possibility that important morphogenetic processes in development, such as symmetry breaking and self‐organization, might be mediated by tissue phase transitions. In this review, we summarize recent findings on the regulation and role of tissue material properties in the context of the developing embryo. We posit that abrupt changes of tissue rheological properties may have important implications in maintaining the balance between robustness and adaptability during embryonic development.}, author = {Petridou, Nicoletta and Heisenberg, Carl-Philipp J}, issn = {1460-2075}, journal = {The EMBO Journal}, number = {20}, publisher = {EMBO}, title = {{Tissue rheology in embryonic organization}}, doi = {10.15252/embj.2019102497}, volume = {38}, year = {2019}, } @inbook{6987, abstract = {Cells are arranged into species-specific patterns during early embryogenesis. Such cell division patterns are important since they often reflect the distribution of localized cortical factors from eggs/fertilized eggs to specific cells as well as the emergence of organismal form. However, it has proven difficult to reveal the mechanisms that underlie the emergence of cell positioning patterns that underlie embryonic shape, likely because a systems-level approach is required that integrates cell biological, genetic, developmental, and mechanical parameters. The choice of organism to address such questions is also important. Because ascidians display the most extreme form of invariant cleavage pattern among the metazoans, we have been analyzing the cell biological mechanisms that underpin three aspects of cell division (unequal cell division (UCD), oriented cell division (OCD), and asynchronous cell cycles) which affect the overall shape of the blastula-stage ascidian embryo composed of 64 cells. In ascidians, UCD creates two small cells at the 16-cell stage that in turn undergo two further successive rounds of UCD. Starting at the 16-cell stage, the cell cycle becomes asynchronous, whereby the vegetal half divides before the animal half, thus creating 24-, 32-, 44-, and then 64-cell stages. Perturbing either UCD or the alternate cell division rhythm perturbs cell position. We propose that dynamic cell shape changes propagate throughout the embryo via cell-cell contacts to create the ascidian-specific invariant cleavage pattern.}, author = {McDougall, Alex and Chenevert, Janet and Godard, Benoit G and Dumollard, Remi}, booktitle = {Evo-Devo: Non-model species in cell and developmental biology}, editor = {Tworzydlo, Waclaw and Bilinski, Szczepan M.}, isbn = {9783030234584}, issn = {1861-0412}, pages = {127--154}, publisher = {Springer Nature}, title = {{Emergence of embryo shape during cleavage divisions}}, doi = {10.1007/978-3-030-23459-1_6}, volume = {68}, year = {2019}, } @phdthesis{7186, abstract = {Tissue morphogenesis in developmental or physiological processes is regulated by molecular and mechanical signals. While the molecular signaling cascades are increasingly well described, the mechanical signals affecting tissue shape changes have only recently been studied in greater detail. To gain more insight into the mechanochemical and biophysical basis of an epithelial spreading process (epiboly) in early zebrafish development, we studied cell-cell junction formation and actomyosin network dynamics at the boundary between surface layer epithelial cells (EVL) and the yolk syncytial layer (YSL). During zebrafish epiboly, the cell mass sitting on top of the yolk cell spreads to engulf the yolk cell by the end of gastrulation. It has been previously shown that an actomyosin ring residing within the YSL pulls on the EVL tissue through a cable-constriction and a flow-friction motor, thereby dragging the tissue vegetal wards. Pulling forces are likely transmitted from the YSL actomyosin ring to EVL cells; however, the nature and formation of the junctional structure mediating this process has not been well described so far. Therefore, our main aim was to determine the nature, dynamics and potential function of the EVL-YSL junction during this epithelial tissue spreading. Specifically, we show that the EVL-YSL junction is a mechanosensitive structure, predominantly made of tight junction (TJ) proteins. The process of TJ mechanosensation depends on the retrograde flow of non-junctional, phase-separated Zonula Occludens-1 (ZO-1) protein clusters towards the EVL-YSL boundary. Interestingly, we could demonstrate that ZO-1 is present in a non-junctional pool on the surface of the yolk cell, and ZO-1 undergoes a phase separation process that likely renders the protein responsive to flows. These flows are directed towards the junction and mediate proper tension-dependent recruitment of ZO-1. Upon reaching the EVL-YSL junction ZO-1 gets incorporated into the junctional pool mediated through its direct actin-binding domain. When the non-junctional pool and/or ZO-1 direct actin binding is absent, TJs fail in their proper mechanosensitive responses resulting in slower tissue spreading. We could further demonstrate that depletion of ZO proteins within the YSL results in diminished actomyosin ring formation. This suggests that a mechanochemical feedback loop is at work during zebrafish epiboly: ZO proteins help in proper actomyosin ring formation and actomyosin contractility and flows positively influence ZO-1 junctional recruitment. Finally, such a mesoscale polarization process mediated through the flow of phase-separated protein clusters might have implications for other processes such as immunological synapse formation, C. elegans zygote polarization and wound healing.}, author = {Schwayer, Cornelia}, issn = {2663-337X}, pages = {107}, publisher = {Institute of Science and Technology Austria}, title = {{Mechanosensation of tight junctions depends on ZO-1 phase separation and flow}}, doi = {10.15479/AT:ISTA:7186}, year = {2019}, } @article{5789, abstract = {Tissue morphogenesis is driven by mechanical forces that elicit changes in cell size, shape and motion. The extent by which forces deform tissues critically depends on the rheological properties of the recipient tissue. Yet, whether and how dynamic changes in tissue rheology affect tissue morphogenesis and how they are regulated within the developing organism remain unclear. Here, we show that blastoderm spreading at the onset of zebrafish morphogenesis relies on a rapid, pronounced and spatially patterned tissue fluidization. Blastoderm fluidization is temporally controlled by mitotic cell rounding-dependent cell–cell contact disassembly during the last rounds of cell cleavages. Moreover, fluidization is spatially restricted to the central blastoderm by local activation of non-canonical Wnt signalling within the blastoderm margin, increasing cell cohesion and thereby counteracting the effect of mitotic rounding on contact disassembly. Overall, our results identify a fluidity transition mediated by loss of cell cohesion as a critical regulator of embryo morphogenesis.}, author = {Petridou, Nicoletta and Grigolon, Silvia and Salbreux, Guillaume and Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {14657392}, journal = {Nature Cell Biology}, pages = {169–178}, publisher = {Nature Publishing Group}, title = {{Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling}}, doi = {10.1038/s41556-018-0247-4}, volume = {21}, year = {2019}, } @article{6508, abstract = {Segregation of maternal determinants within the oocyte constitutes the first step in embryo patterning. In zebrafish oocytes, extensive ooplasmic streaming leads to the segregation of ooplasm from yolk granules along the animal-vegetal axis of the oocyte. Here, we show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the oocyte. This wave functions in segregation by both pulling ooplasm animally and pushing yolk granules vegetally. Using biophysical experimentation and theory, we show that ooplasm pulling is mediated by bulk actin network flows exerting friction forces on the ooplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. Our study defines a novel role of cell-cycle-controlled bulk actin polymerization waves in oocyte polarization via ooplasmic segregation.}, author = {Shamipour, Shayan and Kardos, Roland and Xue, Shi-lei and Hof, Björn and Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {10974172}, journal = {Cell}, number = {6}, pages = {1463--1479.e18}, publisher = {Elsevier}, title = {{Bulk actin dynamics drive phase segregation in zebrafish oocytes}}, doi = {10.1016/j.cell.2019.04.030}, volume = {177}, year = {2019}, } @article{7001, author = {Schwayer, Cornelia and Shamipour, Shayan and Pranjic-Ferscha, Kornelija and Schauer, Alexandra and Balda, M and Tada, M and Matter, K and Heisenberg, Carl-Philipp J}, issn = {1097-4172}, journal = {Cell}, number = {4}, pages = {937--952.e18}, publisher = {Cell Press}, title = {{Mechanosensation of tight junctions depends on ZO-1 phase separation and flow}}, doi = {10.1016/j.cell.2019.10.006}, volume = {179}, year = {2019}, } @article{308, abstract = {Migrating cells penetrate tissue barriers during development, inflammatory responses, and tumor metastasis. We study if migration in vivo in such three-dimensionally confined environments requires changes in the mechanical properties of the surrounding cells using embryonic Drosophila melanogaster hemocytes, also called macrophages, as a model. We find that macrophage invasion into the germband through transient separation of the apposing ectoderm and mesoderm requires cell deformations and reductions in apical tension in the ectoderm. Interestingly, the genetic pathway governing these mechanical shifts acts downstream of the only known tumor necrosis factor superfamily member in Drosophila, Eiger, and its receptor, Grindelwald. Eiger-Grindelwald signaling reduces levels of active Myosin in the germband ectodermal cortex through the localization of a Crumbs complex component, Patj (Pals-1-associated tight junction protein). We therefore elucidate a distinct molecular pathway that controls tissue tension and demonstrate the importance of such regulation for invasive migration in vivo.}, author = {Ratheesh, Aparna and Biebl, Julia and Smutny, Michael and Veselá, Jana and Papusheva, Ekaterina and Krens, Gabriel and Kaufmann, Walter and György, Attila and Casano, Alessandra M and Siekhaus, Daria E}, journal = {Developmental Cell}, number = {3}, pages = {331 -- 346}, publisher = {Elsevier}, title = {{Drosophila TNF modulates tissue tension in the embryo to facilitate macrophage invasive migration}}, doi = {10.1016/j.devcel.2018.04.002}, volume = {45}, year = {2018}, } @article{54, abstract = {During epithelial tissue development, repair, and homeostasis, adherens junctions (AJs) ensure intercellular adhesion and tissue integrity while allowing for cell and tissue dynamics. Mechanical forces play critical roles in AJs’ composition and dynamics. Recent findings highlight that beyond a well-established role in reinforcing cell-cell adhesion, AJ mechanosensitivity promotes junctional remodeling and polarization, thereby regulating critical processes such as cell intercalation, division, and collective migration. Here, we provide an integrated view of mechanosensing mechanisms that regulate cell-cell contact composition, geometry, and integrity under tension and highlight pivotal roles for mechanosensitive AJ remodeling in preserving epithelial integrity and sustaining tissue dynamics.}, author = {Nunes Pinheiro, Diana C and Bellaïche, Yohanns}, journal = {Developmental Cell}, number = {1}, pages = {3 -- 19}, publisher = {Cell Press}, title = {{Mechanical force-driven adherents junction remodeling and epithelial dynamics}}, doi = {10.1016/j.devcel.2018.09.014}, volume = {47}, year = {2018}, } @article{5676, abstract = {In epithelial tissues, cells tightly connect to each other through cell–cell junctions, but they also present the remarkable capacity of reorganizing themselves without compromising tissue integrity. Upon injury, simple epithelia efficiently resolve small lesions through the action of actin cytoskeleton contractile structures at the wound edge and cellular rearrangements. However, the underlying mechanisms and how they cooperate are still poorly understood. In this study, we combine live imaging and theoretical modeling to reveal a novel and indispensable role for occluding junctions (OJs) in this process. We demonstrate that OJ loss of function leads to defects in wound-closure dynamics: instead of contracting, wounds dramatically increase their area. OJ mutants exhibit phenotypes in cell shape, cellular rearrangements, and mechanical properties as well as in actin cytoskeleton dynamics at the wound edge. We propose that OJs are essential for wound closure by impacting on epithelial mechanics at the tissue level, which in turn is crucial for correct regulation of the cellular events occurring at the wound edge.}, author = {Carvalho, Lara and Patricio, Pedro and Ponte, Susana and Heisenberg, Carl-Philipp J and Almeida, Luis and Nunes, André S. and Araújo, Nuno A.M. and Jacinto, Antonio}, issn = {00219525}, journal = {Journal of Cell Biology}, number = {12}, pages = {4267--4283}, publisher = {Rockefeller University Press}, title = {{Occluding junctions as novel regulators of tissue mechanics during wound repair}}, doi = {10.1083/jcb.201804048}, volume = {217}, year = {2018}, } @article{10880, abstract = {Acquisition of evolutionary novelties is a fundamental process for adapting to the external environment and invading new niches and results in the diversification of life, which we can see in the world today. How such novel phenotypic traits are acquired in the course of evolution and are built up in developing embryos has been a central question in biology. Whole-genome duplication (WGD) is a process of genome doubling that supplies raw genetic materials and increases genome complexity. Recently, it has been gradually revealed that WGD and subsequent fate changes of duplicated genes can facilitate phenotypic evolution. Here, we review the current understanding of the relationship between WGD and the acquisition of evolutionary novelties. We show some examples of this link and discuss how WGD and subsequent duplicated genes can facilitate phenotypic evolution as well as when such genomic doubling can be advantageous for adaptation.}, author = {Yuuta, Moriyama and Koshiba-Takeuchi, Kazuko}, issn = {2041-2657}, journal = {Briefings in Functional Genomics}, keywords = {Genetics, Molecular Biology, Biochemistry, General Medicine}, number = {5}, pages = {329--338}, publisher = {Oxford University Press}, title = {{Significance of whole-genome duplications on the emergence of evolutionary novelties}}, doi = {10.1093/bfgp/ely007}, volume = {17}, year = {2018}, } @phdthesis{50, abstract = {The Wnt/planar cell polarity (Wnt/PCP) pathway determines planar polarity of epithelial cells in both vertebrates and invertebrates. The role that Wnt/PCP signaling plays in mesenchymal contexts, however, is only poorly understood. While previous studies have demonstrated the capacity of Wnt/PCP signaling to polarize and guide directed migration of mesenchymal cells, it remains unclear whether endogenous Wnt/PCP signaling performs these functions instructively, as it does in epithelial cells. Here we developed a light-switchable version of the Wnt/PCP receptor Frizzled 7 (Fz7) to unambiguously distinguish between an instructive and a permissive role of Wnt/PCP signaling for the directional collective migration of mesendoderm progenitor cells during zebrafish gastrulation. We show that prechordal plate (ppl) cell migration is defective in maternal-zygotic fz7a and fz7b (MZ fz7a,b) double mutant embryos, and that Fz7 functions cell-autonomously in this process by promoting ppl cell protrusion formation and directed migration. We further show that local activation of Fz7 can direct ppl cell migration both in vitro and in vivo. Surprisingly, however, uniform Fz7 activation is sufficient to fully rescue the ppl cell migration defect in MZ fz7a,b mutant embryos, indicating that Wnt/PCP signaling functions permissively rather than instructively in directed mesendoderm cell migration during zebrafish gastrulation.}, author = {Capek, Daniel}, issn = {2663-337X}, pages = {95}, publisher = {Institute of Science and Technology Austria}, title = {{Optogenetic Frizzled 7 reveals a permissive function of Wnt/PCP signaling in directed mesenchymal cell migration}}, doi = {10.15479/AT:ISTA:TH_1031}, year = {2018}, } @article{678, abstract = {The seminal observation that mechanical signals can elicit changes in biochemical signalling within cells, a process commonly termed mechanosensation and mechanotransduction, has revolutionized our understanding of the role of cell mechanics in various fundamental biological processes, such as cell motility, adhesion, proliferation and differentiation. In this Review, we will discuss how the interplay and feedback between mechanical and biochemical signals control tissue morphogenesis and cell fate specification in embryonic development.}, author = {Petridou, Nicoletta and Spiro, Zoltan P and Heisenberg, Carl-Philipp J}, issn = {14657392}, journal = {Nature Cell Biology}, number = {6}, pages = {581 -- 588}, publisher = {Nature Publishing Group}, title = {{Multiscale force sensing in development}}, doi = {10.1038/ncb3524}, volume = {19}, year = {2017}, } @article{686, abstract = {Tissues are thought to behave like fluids with a given surface tension. Differences in tissue surface tension (TST) have been proposed to trigger cell sorting and tissue envelopment. D'Arcy Thompson in his seminal book ‘On Growth and Form’ has introduced this concept of differential TST as a key physical mechanism dictating tissue formation and organization within the developing organism. Over the past century, many studies have picked up the concept of differential TST and analyzed the role and cell biological basis of TST in development, underlining the importance and influence of this concept in developmental biology.}, author = {Heisenberg, Carl-Philipp J}, issn = {09254773}, journal = {Mechanisms of Development}, pages = {32 -- 37}, publisher = {Elsevier}, title = {{D'Arcy Thompson's ‘on growth and form’: From soap bubbles to tissue self organization}}, doi = {10.1016/j.mod.2017.03.006}, volume = {145}, year = {2017}, } @article{1067, abstract = {Embryo morphogenesis relies on highly coordinated movements of different tissues. However, remarkably little is known about how tissues coordinate their movements to shape the embryo. In zebrafish embryogenesis, coordinated tissue movements first become apparent during “doming,” when the blastoderm begins to spread over the yolk sac, a process involving coordinated epithelial surface cell layer expansion and mesenchymal deep cell intercalations. Here, we find that active surface cell expansion represents the key process coordinating tissue movements during doming. By using a combination of theory and experiments, we show that epithelial surface cells not only trigger blastoderm expansion by reducing tissue surface tension, but also drive blastoderm thinning by inducing tissue contraction through radial deep cell intercalations. Thus, coordinated tissue expansion and thinning during doming relies on surface cells simultaneously controlling tissue surface tension and radial tissue contraction.}, author = {Morita, Hitoshi and Grigolon, Silvia and Bock, Martin and Krens, Gabriel and Salbreux, Guillaume and Heisenberg, Carl-Philipp J}, issn = {15345807}, journal = {Developmental Cell}, number = {4}, pages = {354 -- 366}, publisher = {Cell Press}, title = {{The physical basis of coordinated tissue spreading in zebrafish gastrulation}}, doi = {10.1016/j.devcel.2017.01.010}, volume = {40}, year = {2017}, } @article{1025, abstract = {Many organ surfaces are covered by a protective epithelial-cell layer. It emerges that such layers are maintained by cell stretching that triggers cell division mediated by the force-sensitive ion-channel protein Piezo1. See Letter p.118}, author = {Heisenberg, Carl-Philipp J}, issn = {00280836}, journal = {Nature}, number = {7643}, pages = {43 -- 44}, publisher = {Nature Publishing Group}, title = {{Cell biology: Stretched divisions}}, doi = {10.1038/nature21502}, volume = {543}, year = {2017}, } @article{803, abstract = {Eukaryotic cells store their chromosomes in a single nucleus. This is important to maintain genomic integrity, as chromosomes packaged into separate nuclei (micronuclei) are prone to massive DNA damage. During mitosis, higher eukaryotes disassemble their nucleus and release individualized chromosomes for segregation. How numerous chromosomes subsequently reform a single nucleus has remained unclear. Using image-based screening of human cells, we identified barrier-to-autointegration factor (BAF) as a key factor guiding membranes to form a single nucleus. Unexpectedly, nuclear assembly does not require BAF?s association with inner nuclear membrane proteins but instead relies on BAF?s ability to bridge distant DNA sites. Live-cell imaging and in vitro reconstitution showed that BAF enriches around the mitotic chromosome ensemble to induce a densely cross-bridged chromatin layer that is mechanically stiff and limits membranes to the surface. Our study reveals that BAF-mediated changes in chromosome mechanics underlie nuclear assembly with broad implications for proper genome function.}, author = {Samwer, Matthias and Schneider, Maximilian and Hoefler, Rudolf and Schmalhorst, Philipp S and Jude, Julian and Zuber, Johannes and Gerlic, Daniel}, issn = {00928674}, journal = {Cell}, number = {5}, pages = {956 -- 972}, publisher = {Cell Press}, title = {{DNA cross-bridging shapes a single nucleus from a set of mitotic chromosomes}}, doi = {10.1016/j.cell.2017.07.038}, volume = {170}, year = {2017}, } @article{804, abstract = {Polysaccharides (carbohydrates) are key regulators of a large number of cell biological processes. However, precise biochemical or genetic manipulation of these often complex structures is laborious and hampers experimental structure–function studies. Molecular Dynamics (MD) simulations provide a valuable alternative tool to generate and test hypotheses on saccharide function. Yet, currently used MD force fields often overestimate the aggregation propensity of polysaccharides, affecting the usability of those simulations. Here we tested MARTINI, a popular coarse-grained (CG) force field for biological macromolecules, for its ability to accurately represent molecular forces between saccharides. To this end, we calculated a thermodynamic solution property, the second virial coefficient of the osmotic pressure (B22). Comparison with light scattering experiments revealed a nonphysical aggregation of a prototypical polysaccharide in MARTINI, pointing at an imbalance of the nonbonded solute–solute, solute–water, and water–water interactions. This finding also applies to smaller oligosaccharides which were all found to aggregate in simulations even at moderate concentrations, well below their solubility limit. Finally, we explored the influence of the Lennard-Jones (LJ) interaction between saccharide molecules and propose a simple scaling of the LJ interaction strength that makes MARTINI more reliable for the simulation of saccharides.}, author = {Schmalhorst, Philipp S and Deluweit, Felix and Scherrers, Roger and Heisenberg, Carl-Philipp J and Sikora, Mateusz K}, issn = {15499618}, journal = {Journal of Chemical Theory and Computation}, number = {10}, pages = {5039 -- 5053}, publisher = {American Chemical Society}, title = {{Overcoming the limitations of the MARTINI force field in simulations of polysaccharides}}, doi = {10.1021/acs.jctc.7b00374}, volume = {13}, year = {2017}, } @phdthesis{961, abstract = {Cell-cell contact formation constitutes the first step in the emergence of multicellularity in evolution, thereby allowing the differentiation of specialized cell types. In metazoan development, cell-cell contact formation is thought to influence cell fate specification, and cell fate specification has been implicated in cell-cell contact formation. However, remarkably little is yet known about whether and how the interaction and feedback between cell-cell contact formation and cell fate specification affect development. Here we identify a positive feedback loop between cell-cell contact duration, morphogen signaling and mesendoderm cell fate specification during zebrafish gastrulation. We show that long lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for proper ppl cell fate specification. We further show that Nodal signalling romotes ppl cell-cell contact duration, thereby generating an effective positive feedback loop between ppl cell-cell contact duration and cell fate specification. Finally, by using a combination of theoretical modeling and experimentation, we show that this feedback loop determines whether anterior axial mesendoderm cells become ppl progenitors or, instead, turn into endoderm progenitors. Our findings reveal that the gene regulatory networks leading to cell fate diversification within the developing embryo are controlled by the interdependent activities of cell-cell signaling and contact formation.}, author = {Barone, Vanessa}, issn = {2663-337X}, pages = {109}, publisher = {Institute of Science and Technology Austria}, title = {{Cell adhesion and cell fate: An effective feedback loop during zebrafish gastrulation}}, doi = {10.15479/AT:ISTA:th_825}, year = {2017}, } @article{728, abstract = {During animal development, cell-fate-specific changes in gene expression can modify the material properties of a tissue and drive tissue morphogenesis. While mechanistic insights into the genetic control of tissue-shaping events are beginning to emerge, how tissue morphogenesis and mechanics can reciprocally impact cell-fate specification remains relatively unexplored. Here we review recent findings reporting how multicellular morphogenetic events and their underlying mechanical forces can feed back into gene regulatory pathways to specify cell fate. We further discuss emerging techniques that allow for the direct measurement and manipulation of mechanical signals in vivo, offering unprecedented access to study mechanotransduction during development. Examination of the mechanical control of cell fate during tissue morphogenesis will pave the way to an integrated understanding of the design principles that underlie robust tissue patterning in embryonic development.}, author = {Chan, Chii and Heisenberg, Carl-Philipp J and Hiiragi, Takashi}, issn = {09609822}, journal = {Current Biology}, number = {18}, pages = {R1024 -- R1035}, publisher = {Cell Press}, title = {{Coordination of morphogenesis and cell fate specification in development}}, doi = {10.1016/j.cub.2017.07.010}, volume = {27}, year = {2017}, } @article{729, abstract = {The cellular mechanisms allowing tissues to efficiently regenerate are not fully understood. In this issue of Developmental Cell, Cao et al. (2017)) discover that during zebrafish heart regeneration, epicardial cells at the leading edge of regenerating tissue undergo endoreplication, possibly due to increased tissue tension, thereby boosting their regenerative capacity.}, author = {Spiro, Zoltan P and Heisenberg, Carl-Philipp J}, issn = {15345807}, journal = {Developmental Cell}, number = {6}, pages = {559 -- 560}, publisher = {Cell Press}, title = {{Regeneration tensed up polyploidy takes the lead}}, doi = {10.1016/j.devcel.2017.09.008}, volume = {42}, year = {2017}, } @article{946, abstract = {Roots navigate through soil integrating environmental signals to orient their growth. The Arabidopsis root is a widely used model for developmental, physiological and cell biological studies. Live imaging greatly aids these efforts, but the horizontal sample position and continuous root tip displacement present significant difficulties. Here, we develop a confocal microscope setup for vertical sample mounting and integrated directional illumination. We present TipTracker – a custom software for automatic tracking of diverse moving objects usable on various microscope setups. Combined, this enables observation of root tips growing along the natural gravity vector over prolonged periods of time, as well as the ability to induce rapid gravity or light stimulation. We also track migrating cells in the developing zebrafish embryo, demonstrating the utility of this system in the acquisition of high-resolution data sets of dynamic samples. We provide detailed descriptions of the tools enabling the easy implementation on other microscopes.}, author = {Von Wangenheim, Daniel and Hauschild, Robert and Fendrych, Matyas and Barone, Vanessa and Benková, Eva and Friml, Jirí}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Live tracking of moving samples in confocal microscopy for vertically grown roots}}, doi = {10.7554/eLife.26792}, volume = {6}, year = {2017}, } @article{676, abstract = {The segregation of different cell types into distinct tissues is a fundamental process in metazoan development. Differences in cell adhesion and cortex tension are commonly thought to drive cell sorting by regulating tissue surface tension (TST). However, the role that differential TST plays in cell segregation within the developing embryo is as yet unclear. Here, we have analyzed the role of differential TST for germ layer progenitor cell segregation during zebrafish gastrulation. Contrary to previous observations that differential TST drives germ layer progenitor cell segregation in vitro, we show that germ layers display indistinguishable TST within the gastrulating embryo, arguing against differential TST driving germ layer progenitor cell segregation in vivo. We further show that the osmolarity of the interstitial fluid (IF) is an important factor that influences germ layer TST in vivo, and that lower osmolarity of the IF compared with standard cell culture medium can explain why germ layers display differential TST in culture but not in vivo. Finally, we show that directed migration of mesendoderm progenitors is required for germ layer progenitor cell segregation and germ layer formation.}, author = {Krens, Gabriel and Veldhuis, Jim and Barone, Vanessa and Capek, Daniel and Maître, Jean-Léon and Brodland, Wayne and Heisenberg, Carl-Philipp J}, issn = {09501991}, journal = {Development}, number = {10}, pages = {1798 -- 1806}, publisher = {Company of Biologists}, title = {{Interstitial fluid osmolarity modulates the action of differential tissue surface tension in progenitor cell segregation during gastrulation}}, doi = {10.1242/dev.144964}, volume = {144}, year = {2017}, } @article{661, abstract = {During embryonic development, mechanical forces are essential for cellular rearrangements driving tissue morphogenesis. Here, we show that in the early zebrafish embryo, friction forces are generated at the interface between anterior axial mesoderm (prechordal plate, ppl) progenitors migrating towards the animal pole and neurectoderm progenitors moving in the opposite direction towards the vegetal pole of the embryo. These friction forces lead to global rearrangement of cells within the neurectoderm and determine the position of the neural anlage. Using a combination of experiments and simulations, we show that this process depends on hydrodynamic coupling between neurectoderm and ppl as a result of E-cadherin-mediated adhesion between those tissues. Our data thus establish the emergence of friction forces at the interface between moving tissues as a critical force-generating process shaping the embryo.}, author = {Smutny, Michael and Ákos, Zsuzsa and Grigolon, Silvia and Shamipour, Shayan and Ruprecht, Verena and Capek, Daniel and Behrndt, Martin and Papusheva, Ekaterina and Tada, Masazumi and Hof, Björn and Vicsek, Tamás and Salbreux, Guillaume and Heisenberg, Carl-Philipp J}, issn = {14657392}, journal = {Nature Cell Biology}, pages = {306 -- 317}, publisher = {Nature Publishing Group}, title = {{Friction forces position the neural anlage}}, doi = {10.1038/ncb3492}, volume = {19}, year = {2017}, } @article{735, abstract = {Cell-cell contact formation constitutes an essential step in evolution, leading to the differentiation of specialized cell types. However, remarkably little is known about whether and how the interplay between contact formation and fate specification affects development. Here, we identify a positive feedback loop between cell-cell contact duration, morphogen signaling, and mesendoderm cell-fate specification during zebrafish gastrulation. We show that long-lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for ppl cell-fate specification. We further show that Nodal signaling promotes ppl cell-cell contact duration, generating a positive feedback loop between ppl cell-cell contact duration and cell-fate specification. Finally, by combining mathematical modeling and experimentation, we show that this feedback determines whether anterior axial mesendoderm cells become ppl or, instead, turn into endoderm. Thus, the interdependent activities of cell-cell signaling and contact formation control fate diversification within the developing embryo.}, author = {Barone, Vanessa and Lang, Moritz and Krens, Gabriel and Pradhan, Saurabh and Shamipour, Shayan and Sako, Keisuke and Sikora, Mateusz K and Guet, Calin C and Heisenberg, Carl-Philipp J}, issn = {15345807}, journal = {Developmental Cell}, number = {2}, pages = {198 -- 211}, publisher = {Cell Press}, title = {{An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate}}, doi = {10.1016/j.devcel.2017.09.014}, volume = {43}, year = {2017}, } @article{1239, abstract = {Nonadherent polarized cells have been observed to have a pearlike, elongated shape. Using a minimal model that describes the cell cortex as a thin layer of contractile active gel, we show that the anisotropy of active stresses, controlled by cortical viscosity and filament ordering, can account for this morphology. The predicted shapes can be determined from the flow pattern only; they prove to be independent of the mechanism at the origin of the cortical flow, and are only weakly sensitive to the cytoplasmic rheology. In the case of actin flows resulting from a contractile instability, we propose a phase diagram of three-dimensional cell shapes that encompasses nonpolarized spherical, elongated, as well as oblate shapes, all of which have been observed in experiment.}, author = {Callan Jones, Andrew and Ruprecht, Verena and Wieser, Stefan and Heisenberg, Carl-Philipp J and Voituriez, Raphaël}, journal = {Physical Review Letters}, number = {2}, publisher = {American Physical Society}, title = {{Cortical flow-driven shapes of nonadherent cells}}, doi = {10.1103/PhysRevLett.116.028102}, volume = {116}, year = {2016}, } @article{1249, abstract = {Actin and myosin assemble into a thin layer of a highly dynamic network underneath the membrane of eukaryotic cells. This network generates the forces that drive cell- and tissue-scale morphogenetic processes. The effective material properties of this active network determine large-scale deformations and other morphogenetic events. For example, the characteristic time of stress relaxation (the Maxwell time τM) in the actomyosin sets the timescale of large-scale deformation of the cortex. Similarly, the characteristic length of stress propagation (the hydrodynamic length λ) sets the length scale of slow deformations, and a large hydrodynamic length is a prerequisite for long-ranged cortical flows. Here we introduce a method to determine physical parameters of the actomyosin cortical layer in vivo directly from laser ablation experiments. For this we investigate the cortical response to laser ablation in the one-cell-stage Caenorhabditis elegans embryo and in the gastrulating zebrafish embryo. These responses can be interpreted using a coarse-grained physical description of the cortex in terms of a two-dimensional thin film of an active viscoelastic gel. To determine the Maxwell time τM, the hydrodynamic length λ, the ratio of active stress ζΔμ, and per-area friction γ, we evaluated the response to laser ablation in two different ways: by quantifying flow and density fields as a function of space and time, and by determining the time evolution of the shape of the ablated region. Importantly, both methods provide best-fit physical parameters that are in close agreement with each other and that are similar to previous estimates in the two systems. Our method provides an accurate and robust means for measuring physical parameters of the actomyosin cortical layer. It can be useful for investigations of actomyosin mechanics at the cellular-scale, but also for providing insights into the active mechanics processes that govern tissue-scale morphogenesis.}, author = {Saha, Arnab and Nishikawa, Masatoshi and Behrndt, Martin and Heisenberg, Carl-Philipp J and Julicher, Frank and Grill, Stephan}, journal = {Biophysical Journal}, number = {6}, pages = {1421 -- 1429}, publisher = {Biophysical Society}, title = {{Determining physical properties of the cell cortex}}, doi = {10.1016/j.bpj.2016.02.013}, volume = {110}, year = {2016}, } @article{1271, abstract = {Background: High directional persistence is often assumed to enhance the efficiency of chemotactic migration. Yet, cells in vivo usually display meandering trajectories with relatively low directional persistence, and the control and function of directional persistence during cell migration in three-dimensional environments are poorly understood. Results: Here, we use mesendoderm progenitors migrating during zebrafish gastrulation as a model system to investigate the control of directional persistence during migration in vivo. We show that progenitor cells alternate persistent run phases with tumble phases that result in cell reorientation. Runs are characterized by the formation of directed actin-rich protrusions and tumbles by enhanced blebbing. Increasing the proportion of actin-rich protrusions or blebs leads to longer or shorter run phases, respectively. Importantly, both reducing and increasing run phases result in larger spatial dispersion of the cells, indicative of reduced migration precision. A physical model quantitatively recapitulating the migratory behavior of mesendoderm progenitors indicates that the ratio of tumbling to run times, and thus the specific degree of directional persistence of migration, are critical for optimizing migration precision. Conclusions: Together, our experiments and model provide mechanistic insight into the control of migration directionality for cells moving in three-dimensional environments that combine different protrusion types, whereby the proportion of blebs to actin-rich protrusions determines the directional persistence and precision of movement by regulating the ratio of tumbling to run times.}, author = {Diz Muñoz, Alba and Romanczuk, Pawel and Yu, Weimiao and Bergert, Martin and Ivanovitch, Kenzo and Salbreux, Guillame and Heisenberg, Carl-Philipp J and Paluch, Ewa}, journal = {BMC Biology}, number = {1}, publisher = {BioMed Central}, title = {{Steering cell migration by alternating blebs and actin-rich protrusions}}, doi = {10.1186/s12915-016-0294-x}, volume = {14}, year = {2016}, } @article{1275, author = {Callan Jones, Andrew and Ruprecht, Verena and Wieser, Stefan and Heisenberg, Carl-Philipp J and Voituriez, Raphaël}, journal = {Physical Review Letters}, number = {13}, publisher = {American Physical Society}, title = {{Callan-Jones et al. Reply}}, doi = {10.1103/PhysRevLett.117.139802}, volume = {117}, year = {2016}, } @article{1096, author = {Schwayer, Cornelia and Sikora, Mateusz K and Slovakova, Jana and Kardos, Roland and Heisenberg, Carl-Philipp J}, journal = {Developmental Cell}, number = {6}, pages = {493 -- 506}, publisher = {Cell Press}, title = {{Actin rings of power}}, doi = {10.1016/j.devcel.2016.05.024}, volume = {37}, year = {2016}, } @article{1100, abstract = {During metazoan development, the temporal pattern of morphogen signaling is critical for organizing cell fates in space and time. Yet, tools for temporally controlling morphogen signaling within the embryo are still scarce. Here, we developed a photoactivatable Nodal receptor to determine how the temporal pattern of Nodal signaling affects cell fate specification during zebrafish gastrulation. By using this receptor to manipulate the duration of Nodal signaling in vivo by light, we show that extended Nodal signaling within the organizer promotes prechordal plate specification and suppresses endoderm differentiation. Endoderm differentiation is suppressed by extended Nodal signaling inducing expression of the transcriptional repressor goosecoid (gsc) in prechordal plate progenitors, which in turn restrains Nodal signaling from upregulating the endoderm differentiation gene sox17 within these cells. Thus, optogenetic manipulation of Nodal signaling identifies a critical role of Nodal signaling duration for organizer cell fate specification during gastrulation.}, author = {Sako, Keisuke and Pradhan, Saurabh and Barone, Vanessa and Inglés Prieto, Álvaro and Mueller, Patrick and Ruprecht, Verena and Capek, Daniel and Galande, Sanjeev and Janovjak, Harald L and Heisenberg, Carl-Philipp J}, journal = {Cell Reports}, number = {3}, pages = {866 -- 877}, publisher = {Cell Press}, title = {{Optogenetic control of nodal signaling reveals a temporal pattern of nodal signaling regulating cell fate specification during gastrulation}}, doi = {10.1016/j.celrep.2016.06.036}, volume = {16}, year = {2016}, } @article{1553, abstract = {Cell movement has essential functions in development, immunity, and cancer. Various cell migration patterns have been reported, but no general rule has emerged so far. Here, we show on the basis of experimental data in vitro and in vivo that cell persistence, which quantifies the straightness of trajectories, is robustly coupled to cell migration speed. We suggest that this universal coupling constitutes a generic law of cell migration, which originates in the advection of polarity cues by an actin cytoskeleton undergoing flows at the cellular scale. Our analysis relies on a theoretical model that we validate by measuring the persistence of cells upon modulation of actin flow speeds and upon optogenetic manipulation of the binding of an actin regulator to actin filaments. Beyond the quantitative prediction of the coupling, the model yields a generic phase diagram of cellular trajectories, which recapitulates the full range of observed migration patterns.}, author = {Maiuri, Paolo and Rupprecht, Jean and Wieser, Stefan and Ruprecht, Verena and Bénichou, Olivier and Carpi, Nicolas and Coppey, Mathieu and De Beco, Simon and Gov, Nir and Heisenberg, Carl-Philipp J and Lage Crespo, Carolina and Lautenschlaeger, Franziska and Le Berre, Maël and Lennon Duménil, Ana and Raab, Matthew and Thiam, Hawa and Piel, Matthieu and Sixt, Michael K and Voituriez, Raphaël}, journal = {Cell}, number = {2}, pages = {374 -- 386}, publisher = {Cell Press}, title = {{Actin flows mediate a universal coupling between cell speed and cell persistence}}, doi = {10.1016/j.cell.2015.01.056}, volume = {161}, year = {2015}, } @article{1581, abstract = {In animal embryos, morphogen gradients determine tissue patterning and morphogenesis. Shyer et al. provide evidence that, during vertebrate gut formation, tissue folding generates graded activity of signals required for subsequent steps of gut growth and differentiation, thereby revealing an intriguing link between tissue morphogenesis and morphogen gradient formation.}, author = {Bollenbach, Mark Tobias and Heisenberg, Carl-Philipp J}, journal = {Cell}, number = {3}, pages = {431 -- 432}, publisher = {Cell Press}, title = {{Gradients are shaping up}}, doi = {10.1016/j.cell.2015.04.009}, volume = {161}, year = {2015}, } @article{1817, abstract = {Vertebrates have a unique 3D body shape in which correct tissue and organ shape and alignment are essential for function. For example, vision requires the lens to be centred in the eye cup which must in turn be correctly positioned in the head. Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force. Although a century ago D'Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity, there has been no animal model directly demonstrating how the aforementioned mechano-morphogenetic processes are coordinated to generate a body shape that withstands gravity. Here we report a unique medaka fish (Oryzias latipes) mutant, hirame (hir), which is sensitive to deformation by gravity. hir embryos display a markedly flattened body caused by mutation of YAP, a nuclear executor of Hippo signalling that regulates organ size. We show that actomyosin-mediated tissue tension is reduced in hir embryos, leading to tissue flattening and tissue misalignment, both of which contribute to body flattening. By analysing YAP function in 3D spheroids of human cells, we identify the Rho GTPase activating protein ARHGAP18 as an effector of YAP in controlling tissue tension. Together, these findings reveal a previously unrecognised function of YAP in regulating tissue shape and alignment required for proper 3D body shape. Understanding this morphogenetic function of YAP could facilitate the use of embryonic stem cells to generate complex organs requiring correct alignment of multiple tissues. }, author = {Porazinski, Sean and Wang, Huijia and Asaoka, Yoichi and Behrndt, Martin and Miyamoto, Tatsuo and Morita, Hitoshi and Hata, Shoji and Sasaki, Takashi and Krens, Gabriel and Osada, Yumi and Asaka, Satoshi and Momoi, Akihiro and Linton, Sarah and Miesfeld, Joel and Link, Brian and Senga, Takeshi and Castillo Morales, Atahualpa and Urrutia, Araxi and Shimizu, Nobuyoshi and Nagase, Hideaki and Matsuura, Shinya and Bagby, Stefan and Kondoh, Hisato and Nishina, Hiroshi and Heisenberg, Carl-Philipp J and Furutani Seiki, Makoto}, journal = {Nature}, number = {7551}, pages = {217 -- 221}, publisher = {Nature Publishing Group}, title = {{YAP is essential for tissue tension to ensure vertebrate 3D body shape}}, doi = {10.1038/nature14215}, volume = {521}, year = {2015}, } @article{802, abstract = {Glycoinositolphosphoceramides (GIPCs) are complex sphingolipids present at the plasma membrane of various eukaryotes with the important exception of mammals. In fungi, these glycosphingolipids commonly contain an alpha-mannose residue (Man) linked at position 2 of the inositol. However, several pathogenic fungi additionally synthesize zwitterionic GIPCs carrying an alpha-glucosamine residue (GlcN) at this position. In the human pathogen Aspergillus fumigatus, the GlcNalpha1,2IPC core (where IPC is inositolphosphoceramide) is elongated to Manalpha1,3Manalpha1,6GlcNalpha1,2IPC, which is the most abundant GIPC synthesized by this fungus. In this study, we identified an A. fumigatus N-acetylglucosaminyltransferase, named GntA, and demonstrate its involvement in the initiation of zwitterionic GIPC biosynthesis. Targeted deletion of the gene encoding GntA in A. fumigatus resulted in complete absence of zwitterionic GIPC; a phenotype that could be reverted by episomal expression of GntA in the mutant. The N-acetylhexosaminyltransferase activity of GntA was substantiated by production of N-acetylhexosamine-IPC in the yeast Saccharomyces cerevisiae upon GntA expression. Using an in vitro assay, GntA was furthermore shown to use UDP-N-acetylglucosamine as donor substrate to generate a glycolipid product resistant to saponification and to digestion by phosphatidylinositol-phospholipase C as expected for GlcNAcalpha1,2IPC. Finally, as the enzymes involved in mannosylation of IPC, GntA was localized to the Golgi apparatus, the site of IPC synthesis.}, author = {Engel, Jakob and Schmalhorst, Philipp S and Kruger, Anke and Muller, Christina and Buettner, Falk and Routier, Françoise}, journal = {Glycobiology}, number = {12}, pages = {1423 -- 1430}, publisher = {Oxford University Press}, title = {{Characterization of an N-acetylglucosaminyltransferase involved in Aspergillus fumigatus zwitterionic glycoinositolphosphoceramide biosynthesis}}, doi = {10.1093/glycob/cwv059}, volume = {25}, year = {2015}, } @article{1566, abstract = {Deposits of misfolded proteins in the human brain are associated with the development of many neurodegenerative diseases. Recent studies show that these proteins have common traits even at the monomer level. Among them, a polyglutamine region that is present in huntingtin is known to exhibit a correlation between the length of the chain and the severity as well as the earliness of the onset of Huntington disease. Here, we apply bias exchange molecular dynamics to generate structures of polyglutamine expansions of several lengths and characterize the resulting independent conformations. We compare the properties of these conformations to those of the standard proteins, as well as to other homopolymeric tracts. We find that, similar to the previously studied polyvaline chains, the set of possible transient folds is much broader than the set of known-to-date folds, although the conformations have different structures. We show that the mechanical stability is not related to any simple geometrical characteristics of the structures. We demonstrate that long polyglutamine expansions result in higher mechanical stability than the shorter ones. They also have a longer life span and are substantially more prone to form knotted structures. The knotted region has an average length of 35 residues, similar to the typical threshold for most polyglutamine-related diseases. Similarly, changes in shape and mechanical stability appear once the total length of the peptide exceeds this threshold of 35 glutamine residues. We suggest that knotted conformers may also harm the cellular machinery and thus lead to disease.}, author = {Gómez Sicilia, Àngel and Sikora, Mateusz K and Cieplak, Marek and Carrión Vázquez, Mariano}, journal = {PLoS Computational Biology}, number = {10}, publisher = {Public Library of Science}, title = {{An exploration of the universe of polyglutamine structures}}, doi = {10.1371/journal.pcbi.1004541}, volume = {11}, year = {2015}, } @misc{9714, author = {Gómez Sicilia, Àngel and Sikora, Mateusz K and Cieplak, Marek and Carrión Vázquez, Mariano}, publisher = {Public Library of Science }, title = {{An exploration of the universe of polyglutamine structures - submission to PLOS journals}}, doi = {10.1371/journal.pcbi.1004541.s001}, year = {2015}, } @article{1537, abstract = {3D amoeboid cell migration is central to many developmental and disease-related processes such as cancer metastasis. Here, we identify a unique prototypic amoeboid cell migration mode in early zebrafish embryos, termed stable-bleb migration. Stable-bleb cells display an invariant polarized balloon-like shape with exceptional migration speed and persistence. Progenitor cells can be reversibly transformed into stable-bleb cells irrespective of their primary fate and motile characteristics by increasing myosin II activity through biochemical or mechanical stimuli. Using a combination of theory and experiments, we show that, in stable-bleb cells, cortical contractility fluctuations trigger a stochastic switch into amoeboid motility, and a positive feedback between cortical flows and gradients in contractility maintains stable-bleb cell polarization. We further show that rearward cortical flows drive stable-bleb cell migration in various adhesive and non-adhesive environments, unraveling a highly versatile amoeboid migration phenotype.}, author = {Ruprecht, Verena and Wieser, Stefan and Callan Jones, Andrew and Smutny, Michael and Morita, Hitoshi and Sako, Keisuke and Barone, Vanessa and Ritsch Marte, Monika and Sixt, Michael K and Voituriez, Raphaël and Heisenberg, Carl-Philipp J}, journal = {Cell}, number = {4}, pages = {673 -- 685}, publisher = {Cell Press}, title = {{Cortical contractility triggers a stochastic switch to fast amoeboid cell motility}}, doi = {10.1016/j.cell.2015.01.008}, volume = {160}, year = {2015}, } @article{10815, abstract = {In the last several decades, developmental biology has clarified the molecular mechanisms of embryogenesis and organogenesis. In particular, it has demonstrated that the “tool-kit genes” essential for regulating developmental processes are not only highly conserved among species, but are also used as systems at various times and places in an organism to control distinct developmental events. Therefore, mutations in many of these tool-kit genes may cause congenital diseases involving morphological abnormalities. This link between genes and abnormal morphological phenotypes underscores the importance of understanding how cells behave and contribute to morphogenesis as a result of gene function. Recent improvements in live imaging and in quantitative analyses of cellular dynamics will advance our understanding of the cellular pathogenesis of congenital diseases associated with aberrant morphologies. In these studies, it is critical to select an appropriate model organism for the particular phenomenon of interest.}, author = {Hashimoto, Masakazu and Morita, Hitoshi and Ueno, Naoto}, issn = {0914-3505}, journal = {Congenital Anomalies}, keywords = {Developmental Biology, Embryology, General Medicine, Pediatrics, Perinatology, and Child Health}, number = {1}, pages = {1--7}, publisher = {Wiley}, title = {{Molecular and cellular mechanisms of development underlying congenital diseases}}, doi = {10.1111/cga.12039}, volume = {54}, year = {2014}, } @article{1891, abstract = {We provide theoretical tests of a novel experimental technique to determine mechanostability of proteins based on stretching a mechanically protected protein by single-molecule force spectroscopy. This technique involves stretching a homogeneous or heterogeneous chain of reference proteins (single-molecule markers) in which one of them acts as host to the guest protein under study. The guest protein is grafted into the host through genetic engineering. It is expected that unraveling of the host precedes the unraveling of the guest removing ambiguities in the reading of the force-extension patterns of the guest protein. We study examples of such systems within a coarse-grained structure-based model. We consider systems with various ratios of mechanostability for the host and guest molecules and compare them to experimental results involving cohesin I as the guest molecule. For a comparison, we also study the force-displacement patterns in proteins that are linked in a serial fashion. We find that the mechanostability of the guest is similar to that of the isolated or serially linked protein. We also demonstrate that the ideal configuration of this strategy would be one in which the host is much more mechanostable than the single-molecule markers. We finally show that it is troublesome to use the highly stable cystine knot proteins as a host to graft a guest in stretching studies because this would involve a cleaving procedure.}, author = {Chwastyk, Mateusz and Galera Prat, Albert and Sikora, Mateusz K and Gómez Sicilia, Àngel and Carrión Vázquez, Mariano and Cieplak, Marek}, journal = {Proteins: Structure, Function and Bioinformatics}, number = {5}, pages = {717 -- 726}, publisher = {Wiley-Blackwell}, title = {{Theoretical tests of the mechanical protection strategy in protein nanomechanics}}, doi = {10.1002/prot.24436}, volume = {82}, year = {2014}, } @article{1900, abstract = {Epithelial cell layers need to be tightly regulated to maintain their integrity and correct function. Cell integration into epithelial sheets is now shown to depend on the N-WASP-regulated stabilization of cortical F-actin, which generates distinct patterns of apical-lateral contractility at E-cadherin-based cell-cell junctions.}, author = {Behrndt, Martin and Heisenberg, Carl-Philipp J}, journal = {Nature Cell Biology}, number = {2}, pages = {127 -- 129}, publisher = {Nature Publishing Group}, title = {{Lateral junction dynamics lead the way out}}, doi = {10.1038/ncb2913}, volume = {16}, year = {2014}, } @article{1925, abstract = {In the past decade carbon nanotubes (CNTs) have been widely studied as a potential drug-delivery system, especially with functionality for cellular targeting. Yet, little is known about the actual process of docking to cell receptors and transport dynamics after internalization. Here we performed single-particle studies of folic acid (FA) mediated CNT binding to human carcinoma cells and their transport inside the cytosol. In particular, we employed molecular recognition force spectroscopy, an atomic force microscopy based method, to visualize and quantify docking of FA functionalized CNTs to FA binding receptors in terms of binding probability and binding force. We then traced individual fluorescently labeled, FA functionalized CNTs after specific uptake, and created a dynamic 'roadmap' that clearly showed trajectories of directed diffusion and areas of nanotube confinement in the cytosol. Our results demonstrate the potential of a single-molecule approach for investigation of drug-delivery vehicles and their targeting capacity.}, author = {Lamprecht, Constanze and Plochberger, Birgit and Ruprecht, Verena and Wieser, Stefan and Rankl, Christian and Heister, Elena and Unterauer, Barbara and Brameshuber, Mario and Danzberger, Jürgen and Lukanov, Petar and Flahaut, Emmanuel and Schütz, Gerhard and Hinterdorfer, Peter and Ebner, Andreas}, journal = {Nanotechnology}, number = {12}, publisher = {IOP Publishing}, title = {{A single-molecule approach to explore binding uptake and transport of cancer cell targeting nanotubes}}, doi = {10.1088/0957-4484/25/12/125704}, volume = {25}, year = {2014}, } @article{1923, abstract = {We derive the equations for a thin, axisymmetric elastic shell subjected to an internal active stress giving rise to active tension and moments within the shell. We discuss the stability of a cylindrical elastic shell and its response to a localized change in internal active stress. This description is relevant to describe the cellular actomyosin cortex, a thin shell at the cell surface behaving elastically at a short timescale and subjected to active internal forces arising from myosin molecular motor activity. We show that the recent observations of cell deformation following detachment of adherent cells (Maître J-L et al 2012 Science 338 253-6) are well accounted for by this mechanical description. The actin cortex elastic and bending moduli can be obtained from a quantitative analysis of cell shapes observed in these experiments. Our approach thus provides a non-invasive, imaging-based method for the extraction of cellular physical parameters.}, author = {Berthoumieux, Hélène and Maître, Jean-Léon and Heisenberg, Carl-Philipp J and Paluch, Ewa and Julicher, Frank and Salbreux, Guillaume}, journal = {New Journal of Physics}, publisher = {IOP Publishing Ltd.}, title = {{Active elastic thin shell theory for cellular deformations}}, doi = {10.1088/1367-2630/16/6/065005}, volume = {16}, year = {2014}, } @article{2248, abstract = {Avian forelimb digit homology remains one of the standard themes in comparative biology and EvoDevo research. In order to resolve the apparent contradictions between embryological and paleontological evidence a variety of hypotheses have been presented in recent years. The proposals range from excluding birds from the dinosaur clade, to assignments of homology by different criteria, or even assuming a hexadactyl tetrapod limb ground state. At present two approaches prevail: the frame shift hypothesis and the pyramid reduction hypothesis. While the former postulates a homeotic shift of digit identities, the latter argues for a gradual bilateral reduction of phalanges and digits. Here we present a new model that integrates elements from both hypotheses with the existing experimental and fossil evidence. We start from the main feature common to both earlier concepts, the initiating ontogenetic event: reduction and loss of the anterior-most digit. It is proposed that a concerted mechanism of molecular regulation and developmental mechanics is capable of shifting the boundaries of hoxD expression in embryonic forelimb buds as well as changing the digit phenotypes. Based on a distinction between positional (topological) and compositional (phenotypic) homology criteria, we argue that the identity of the avian digits is II, III, IV, despite a partially altered phenotype. Finally, we introduce an alternative digit reduction scheme that reconciles the current fossil evidence with the presented molecular-morphogenetic model. Our approach identifies specific experiments that allow to test whether gene expression can be shifted and digit phenotypes can be altered by induced digit loss or digit gain.}, author = {Capek, Daniel and Metscher, Brian and Müller, Gerd}, issn = {15525007}, journal = {Journal of Experimental Zoology Part B: Molecular and Developmental Evolution}, number = {1}, pages = {1 -- 12}, publisher = {Wiley-Blackwell}, title = {{Thumbs down: A molecular-morphogenetic approach to avian digit homology}}, doi = {10.1002/jez.b.22545}, volume = {322}, year = {2014}, } @inbook{6178, abstract = {Mechanically coupled cells can generate forces driving cell and tissue morphogenesis during development. Visualization and measuring of these forces is of major importance to better understand the complexity of the biomechanic processes that shape cells and tissues. Here, we describe how UV laser ablation can be utilized to quantitatively assess mechanical tension in different tissues of the developing zebrafish and in cultures of primary germ layer progenitor cells ex vivo.}, author = {Smutny, Michael and Behrndt, Martin and Campinho, Pedro and Ruprecht, Verena and Heisenberg, Carl-Philipp J}, booktitle = {Tissue Morphogenesis}, editor = {Nelson, Celeste}, isbn = {9781493911639}, issn = {1940-6029}, pages = {219--235}, publisher = {Springer}, title = {{UV laser ablation to measure cell and tissue-generated forces in the zebrafish embryo in vivo and ex vivo}}, doi = {10.1007/978-1-4939-1164-6_15}, volume = {1189}, year = {2014}, } @article{1912, abstract = {Kupffer's vesicle (KV) is the zebrafish organ of laterality, patterning the embryo along its left-right (LR) axis. Regional differences in cell shape within the lumen-lining KV epithelium are essential for its LR patterning function. However, the processes by which KV cells acquire their characteristic shapes are largely unknown. Here, we show that the notochord induces regional differences in cell shape within KV by triggering extracellular matrix (ECM) accumulation adjacent to anterior-dorsal (AD) regions of KV. This localized ECM deposition restricts apical expansion of lumen-lining epithelial cells in AD regions of KV during lumen growth. Our study provides mechanistic insight into the processes by which KV translates global embryonic patterning into regional cell shape differences required for its LR symmetry-breaking function.}, author = {Compagnon, Julien and Barone, Vanessa and Rajshekar, Srivarsha and Kottmeier, Rita and Pranjic-Ferscha, Kornelija and Behrndt, Martin and Heisenberg, Carl-Philipp J}, journal = {Developmental Cell}, number = {6}, pages = {774 -- 783}, publisher = {Cell Press}, title = {{The notochord breaks bilateral symmetry by controlling cell shapes in the Zebrafish laterality organ}}, doi = {10.1016/j.devcel.2014.11.003}, volume = {31}, year = {2014}, } @phdthesis{1403, abstract = {A variety of developmental and disease related processes depend on epithelial cell sheet spreading. In order to gain insight into the biophysical mechanism(s) underlying the tissue morphogenesis we studied the spreading of an epithelium during the early development of the zebrafish embryo. In zebrafish epiboly the enveloping cell layer (EVL), a simple squamous epithelium, spreads over the yolk cell to completely engulf it at the end of gastrulation. Previous studies have proposed that an actomyosin ring forming within the yolk syncytial layer (YSL) acts as purse string that through constriction along its circumference pulls on the margin of the EVL. Direct biophysical evidence for this hypothesis has however been missing. The aim of the thesis was to understand how the actomyosin ring may generate pulling forces onto the EVL and what cellular mechanism(s) may facilitate the spreading of the epithelium. Using laser ablation to measure cortical tension within the actomyosin ring we found an anisotropic tension distribution, which was highest along the circumference of the ring. However the low degree of anisotropy was incompatible with the actomyosin ring functioning as a purse string only. Additionally, we observed retrograde cortical flow from vegetal parts of the ring into the EVL margin. Interpreting the experimental data using a theoretical distribution that models the tissues as active viscous gels led us to proposen that the actomyosin ring has a twofold contribution to EVL epiboly. It not only acts as a purse string through constriction along its circumference, but in addition constriction along the width of the ring generates pulling forces through friction-resisted cortical flow. Moreover, when rendering the purse string mechanism unproductive EVL epiboly proceeded normally indicating that the flow-friction mechanism is sufficient to drive the process. Aiming to understand what cellular mechanism(s) may facilitate the spreading of the epithelium we found that tension-oriented EVL cell divisions limit tissue anisotropy by releasing tension along the division axis and promote epithelial spreading. Notably, EVL cells undergo ectopic cell fusion in conditions in which oriented-cell division is impaired or the epithelium is mechanically challenged. Taken together our study of EVL epiboly suggests a novel mechanism of force generation for actomyosin rings through friction-resisted cortical flow and highlights the importance of tension-oriented cell divisions in epithelial morphogenesis.}, author = {Behrndt, Martin}, pages = {91}, publisher = {IST Austria}, title = {{Forces driving epithelial spreading in zebrafish epiboly}}, year = {2014}, } @article{2278, abstract = {It is firmly established that interactions between neurons and glia are fundamental across species for the correct establishment of a functional brain. Here, we found that the glia of the Drosophila larval brain display an essential non-autonomous role during the development of the optic lobe. The optic lobe develops from neuroepithelial cells that proliferate by dividing symmetrically until they switch to asymmetric/differentiative divisions that generate neuroblasts. The proneural gene lethal of scute (l9sc) is transiently activated by the epidermal growth factor receptor (EGFR)-Ras signal transduction pathway at the leading edge of a proneural wave that sweeps from medial to lateral neuroepithelium, promoting this switch. This process is tightly regulated by the tissue-autonomous function within the neuroepithelium of multiple signaling pathways, including EGFR-Ras and Notch. This study shows that the Notch ligand Serrate (Ser) is expressed in the glia and it forms a complex in vivo with Notch and Canoe, which colocalize at the adherens junctions of neuroepithelial cells. This complex is crucial for interactions between glia and neuroepithelial cells during optic lobe development. Ser is tissue-autonomously required in the glia where it activates Notch to regulate its proliferation, and non-autonomously in the neuroepithelium where Ser induces Notch signaling to avoid the premature activation of the EGFR-Ras pathway and hence of L9sc. Interestingly, different Notch activity reporters showed very different expression patterns in the glia and in the neuroepithelium, suggesting the existence of tissue-specific factors that promote the expression of particular Notch target genes or/and a reporter response dependent on different thresholds of Notch signaling.}, author = {Pérez Gómez, Raquel and Slovakova, Jana and Rives Quinto, Noemí and Krejčí, Alena and Carmena, Ana}, journal = {Journal of Cell Science}, number = {21}, pages = {4873 -- 4884}, publisher = {Company of Biologists}, title = {{A serrate-notch-canoe complex mediates essential interactions between glia and neuroepithelial cells during Drosophila optic lobe development}}, doi = {10.1242/jcs.125617}, volume = {126}, year = {2013}, } @article{2282, abstract = {Epithelial spreading is a common and fundamental aspect of various developmental and disease-related processes such as epithelial closure and wound healing. A key challenge for epithelial tissues undergoing spreading is to increase their surface area without disrupting epithelial integrity. Here we show that orienting cell divisions by tension constitutes an efficient mechanism by which the enveloping cell layer (EVL) releases anisotropic tension while undergoing spreading during zebrafish epiboly. The control of EVL cell-division orientation by tension involves cell elongation and requires myosin II activity to align the mitotic spindle with the main tension axis. We also found that in the absence of tension-oriented cell divisions and in the presence of increased tissue tension, EVL cells undergo ectopic fusions, suggesting that the reduction of tension anisotropy by oriented cell divisions is required to prevent EVL cells from fusing. We conclude that cell-division orientation by tension constitutes a key mechanism for limiting tension anisotropy and thus promoting tissue spreading during EVL epiboly.}, author = {Campinho, Pedro and Behrndt, Martin and Ranft, Jonas and Risler, Thomas and Minc, Nicolas and Heisenberg, Carl-Philipp J}, journal = {Nature Cell Biology}, pages = {1405 -- 1414}, publisher = {Nature Publishing Group}, title = {{Tension-oriented cell divisions limit anisotropic tissue tension in epithelial spreading during zebrafish epiboly}}, doi = {10.1038/ncb2869}, volume = {15}, year = {2013}, } @article{2286, abstract = {The spatiotemporal control of cell divisions is a key factor in epithelial morphogenesis and patterning. Mao et al (2013) now describe how differential rates of proliferation within the Drosophila wing disc epithelium give rise to anisotropic tissue tension in peripheral/proximal regions of the disc. Such global tissue tension anisotropy in turn determines the orientation of cell divisions by controlling epithelial cell elongation.}, author = {Campinho, Pedro and Heisenberg, Carl-Philipp J}, journal = {EMBO Journal}, number = {21}, pages = {2783 -- 2784}, publisher = {Wiley-Blackwell}, title = {{The force and effect of cell proliferation}}, doi = {10.1038/emboj.2013.225}, volume = {32}, year = {2013}, } @article{2469, abstract = {Cadherins are transmembrane proteins that mediate cell–cell adhesion in animals. By regulating contact formation and stability, cadherins play a crucial role in tissue morphogenesis and homeostasis. Here, we review the three major unctions of cadherins in cell–cell contact formation and stability. Two of those functions lead to a decrease in interfacial ension at the forming cell–cell contact, thereby promoting contact expansion — first, by providing adhesion tension that lowers interfacial tension at the cell–cell contact, and second, by signaling to the actomyosin cytoskeleton in order to reduce cortex tension and thus interfacial tension at the contact. The third function of cadherins in cell–cell contact formation is to stabilize the contact by resisting mechanical forces that pull on the contact.}, author = {Maître, Jean-Léon and Heisenberg, Carl-Philipp J}, journal = {Current Biology}, number = {14}, pages = {R626 -- R633}, publisher = {Cell Press}, title = {{Three functions of cadherins in cell adhesion}}, doi = {10.1016/j.cub.2013.06.019}, volume = {23}, year = {2013}, } @article{2833, abstract = {During development, mechanical forces cause changes in size, shape, number, position, and gene expression of cells. They are therefore integral to any morphogenetic processes. Force generation by actin-myosin networks and force transmission through adhesive complexes are two self-organizing phenomena driving tissue morphogenesis. Coordination and integration of forces by long-range force transmission and mechanosensing of cells within tissues produce large-scale tissue shape changes. Extrinsic mechanical forces also control tissue patterning by modulating cell fate specification and differentiation. Thus, the interplay between tissue mechanics and biochemical signaling orchestrates tissue morphogenesis and patterning in development.}, author = {Heisenberg, Carl-Philipp J and Bellaïche, Yohanns}, journal = {Cell}, number = {5}, pages = {948 -- 962}, publisher = {Cell Press}, title = {{Forces in tissue morphogenesis and patterning}}, doi = {10.1016/j.cell.2013.05.008}, volume = {153}, year = {2013}, } @article{2841, abstract = {In zebrafish early development, blastoderm cells undergo extensive radial intercalations, triggering the spreading of the blastoderm over the yolk cell and thereby initiating embryonic body axis formation. Now reporting in Developmental Cell, Song et al. (2013) demonstrate a critical function for EGF-dependent E-cadherin endocytosis in promoting blastoderm cell intercalations.}, author = {Morita, Hitoshi and Heisenberg, Carl-Philipp J}, journal = {Developmental Cell}, number = {6}, pages = {567 -- 569}, publisher = {Cell Press}, title = {{Holding on and letting go: Cadherin turnover in cell intercalation}}, doi = {10.1016/j.devcel.2013.03.007}, volume = {24}, year = {2013}, } @article{2862, abstract = {Motile cilia perform crucial functions during embryonic development and throughout adult life. Development of organs containing motile cilia involves regulation of cilia formation (ciliogenesis) and formation of a luminal space (lumenogenesis) in which cilia generate fluid flows. Control of ciliogenesis and lumenogenesis is not yet fully understood, and it remains unclear whether these processes are coupled. In the zebrafish embryo, lethal giant larvae 2 (lgl2) is expressed prominently in ciliated organs. Lgl proteins are involved in establishing cell polarity and have been implicated in vesicle trafficking. Here, we identified a role for Lgl2 in development of ciliated epithelia in Kupffer's vesicle, which directs left-right asymmetry of the embryo; the otic vesicles, which give rise to the inner ear; and the pronephric ducts of the kidney. Using Kupffer's vesicle as a model ciliated organ, we found that depletion of Lgl2 disrupted lumen formation and reduced cilia number and length. Immunofluorescence and time-lapse imaging of Kupffer's vesicle morphogenesis in Lgl2-deficient embryos suggested cell adhesion defects and revealed loss of the adherens junction component E-cadherin at lateral membranes. Genetic interaction experiments indicate that Lgl2 interacts with Rab11a to regulate E-cadherin and mediate lumen formation that is uncoupled from cilia formation. These results uncover new roles and interactions for Lgl2 that are crucial for both lumenogenesis and ciliogenesis and indicate that these processes are genetically separable in zebrafish.}, author = {Tay, Hwee and Schulze, Sabrina and Compagnon, Julien and Foley, Fiona and Heisenberg, Carl-Philipp J and Yost, H Joseph and Abdelilah Seyfried, Salim and Amack, Jeffrey}, journal = {Development}, number = {7}, pages = {1550 -- 1559}, publisher = {Company of Biologists}, title = {{Lethal giant larvae 2 regulates development of the ciliated organ Kupffer’s vesicle}}, doi = {10.1242/dev.087130}, volume = {140}, year = {2013}, } @article{2884, author = {Maître, Jean-Léon and Berthoumieux, Hélène and Krens, Gabriel and Salbreux, Guillaume and Julicher, Frank and Paluch, Ewa and Heisenberg, Carl-Philipp J}, journal = {Medecine Sciences}, number = {2}, pages = {147 -- 150}, publisher = {Éditions Médicales et Scientifiques}, title = {{Cell adhesion mechanics of zebrafish gastrulation}}, doi = {10.1051/medsci/2013292011}, volume = {29}, year = {2013}, } @article{2918, abstract = {Oriented mitosis is essential during tissue morphogenesis. The Wnt/planar cell polarity (Wnt/PCP) pathway orients mitosis in a number of developmental systems, including dorsal epiblast cell divisions along the animal-vegetal (A-V) axis during zebrafish gastrulation. How Wnt signalling orients the mitotic plane is, however, unknown. Here we show that, in dorsal epiblast cells, anthrax toxin receptor 2a (Antxr2a) accumulates in a polarized cortical cap, which is aligned with the embryonic A-V axis and forecasts the division plane. Filamentous actin (F-actin) also forms an A-V polarized cap, which depends on Wnt/PCP and its effectors RhoA and Rock2. Antxr2a is recruited to the cap by interacting with actin. Antxr2a also interacts with RhoA and together they activate the diaphanous-related formin zDia2. Mechanistically, Antxr2a functions as a Wnt-dependent polarized determinant, which, through the action of RhoA and zDia2, exerts torque on the spindle to align it with the A-V axis. }, author = {Castanon, Irinka and Abrami, Laurence and Holtzer, Laurent and Heisenberg, Carl-Philipp J and Van Der Goot, Françoise and González Gaitán, Marcos}, journal = {Nature Cell Biology}, number = {1}, pages = {28 -- 39}, publisher = {Nature Publishing Group}, title = {{Anthrax toxin receptor 2a controls mitotic spindle positioning}}, doi = {10.1038/ncb2632}, volume = {15}, year = {2013}, } @article{2920, abstract = {Cell polarisation in development is a common and fundamental process underlying embryo patterning and morphogenesis, and has been extensively studied over the past years. Our current knowledge of cell polarisation in development is predominantly based on studies that have analysed polarisation of single cells, such as eggs, or cellular aggregates with a stable polarising interface, such as cultured epithelial cells (St Johnston and Ahringer, 2010). However, in embryonic development, particularly of vertebrates, cell polarisation processes often encompass large numbers of cells that are placed within moving and proliferating tissues, and undergo mesenchymal-to-epithelial transitions with a highly complex spatiotemporal choreography. How such intricate cell polarisation processes in embryonic development are achieved has only started to be analysed. By using live imaging of neurulation in the transparent zebrafish embryo, Buckley et al (2012) now describe a novel polarisation strategy by which cells assemble an apical domain in the part of their cell body that intersects with the midline of the forming neural rod. This mechanism, along with the previously described mirror-symmetric divisions (Tawk et al, 2007), is thought to trigger formation of both neural rod midline and lumen.}, author = {Compagnon, Julien and Heisenberg, Carl-Philipp J}, journal = {EMBO Journal}, number = {1}, pages = {1 -- 3}, publisher = {Wiley-Blackwell}, title = {{Neurulation coordinating cell polarisation and lumen formation}}, doi = {10.1038/emboj.2012.325}, volume = {32}, year = {2013}, } @phdthesis{1406, abstract = {Epithelial spreading is a critical part of various developmental and wound repair processes. Here we use zebrafish epiboly as a model system to study the cellular and molecular mechanisms underlying the spreading of epithelial sheets. During zebrafish epiboly the enveloping cell layer (EVL), a simple squamous epithelium, spreads over the embryo to eventually cover the entire yolk cell by the end of gastrulation. The EVL leading edge is anchored through tight junctions to the yolk syncytial layer (YSL), where directly adjacent to the EVL margin a contractile actomyosin ring is formed that is thought to drive EVL epiboly. The prevalent view in the field was that the contractile ring exerts a pulling force on the EVL margin, which pulls the EVL towards the vegetal pole. However, how this force is generated and how it affects EVL morphology still remains elusive. Moreover, the cellular mechanisms mediating the increase in EVL surface area, while maintaining tissue integrity and function are still unclear. Here we show that the YSL actomyosin ring pulls on the EVL margin by two distinct force-generating mechanisms. One mechanism is based on contraction of the ring around its circumference, as previously proposed. The second mechanism is based on actomyosin retrogade flows, generating force through resistance against the substrate. The latter can function at any epiboly stage even in situations where the contraction-based mechanism is unproductive. Additionally, we demonstrate that during epiboly the EVL is subjected to anisotropic tension, which guides the orientation of EVL cell division along the main axis (animal-vegetal) of tension. The influence of tension in cell division orientation involves cell elongation and requires myosin-2 activity for proper spindle alignment. Strikingly, we reveal that tension-oriented cell divisions release anisotropic tension within the EVL and that in the absence of such divisions, EVL cells undergo ectopic fusions. We conclude that forces applied to the EVL by the action of the YSL actomyosin ring generate a tension anisotropy in the EVL that orients cell divisions, which in turn limit tissue tension increase thereby facilitating tissue spreading.}, author = {Campinho, Pedro}, issn = {2663-337X}, pages = {123}, publisher = {Institute of Science and Technology Austria}, title = {{Mechanics of zebrafish epiboly: Tension-oriented cell divisions limit anisotropic tissue tension in epithelial spreading}}, year = {2013}, } @article{2926, abstract = {To fight infectious diseases, host immune defenses are employed at multiple levels. Sanitary behavior, such as pathogen avoidance and removal, acts as a first line of defense to prevent infection [1] before activation of the physiological immune system. Insect societies have evolved a wide range of collective hygiene measures and intensive health care toward pathogen-exposed group members [2]. One of the most common behaviors is allogrooming, in which nestmates remove infectious particles from the body surfaces of exposed individuals [3]. Here we show that, in invasive garden ants, grooming of fungus-exposed brood is effective beyond the sheer mechanical removal of fungal conidiospores; it also includes chemical disinfection through the application of poison produced by the ants themselves. Formic acid is the main active component of the poison. It inhibits fungal growth of conidiospores remaining on the brood surface after grooming and also those collected in the mouth of the grooming ant. This dual function is achieved by uptake of the poison droplet into the mouth through acidopore self-grooming and subsequent application onto the infectious brood via brood grooming. This extraordinary behavior extends the current understanding of grooming and the establishment of social immunity in insect societies.}, author = {Tragust, Simon and Mitteregger, Barbara and Barone, Vanessa and Konrad, Matthias and Ugelvig, Line V and Cremer, Sylvia}, journal = {Current Biology}, number = {1}, pages = {76 -- 82}, publisher = {Cell Press}, title = {{Ants disinfect fungus-exposed brood by oral uptake and spread of their poison}}, doi = {10.1016/j.cub.2012.11.034}, volume = {23}, year = {2013}, } @article{2950, abstract = {Contractile actomyosin rings drive various fundamental morphogenetic processes ranging from cytokinesis to wound healing. Actomyosin rings are generally thought to function by circumferential contraction. Here, we show that the spreading of the enveloping cell layer (EVL) over the yolk cell during zebrafish gastrulation is driven by a contractile actomyosin ring. In contrast to previous suggestions, we find that this ring functions not only by circumferential contraction but also by a flow-friction mechanism. This generates a pulling force through resistance against retrograde actomyosin flow. EVL spreading proceeds normally in situations where circumferential contraction is unproductive, indicating that the flow-friction mechanism is sufficient. Thus, actomyosin rings can function in epithelial morphogenesis through a combination of cable-constriction and flow-friction mechanisms.}, author = {Behrndt, Martin and Salbreux, Guillaume and Campinho, Pedro and Hauschild, Robert and Oswald, Felix and Roensch, Julia and Grill, Stephan and Heisenberg, Carl-Philipp J}, journal = {Science}, number = {6104}, pages = {257 -- 260}, publisher = {American Association for the Advancement of Science}, title = {{Forces driving epithelial spreading in zebrafish gastrulation}}, doi = {10.1126/science.1224143}, volume = {338}, year = {2012}, } @article{2951, abstract = {Differential cell adhesion and cortex tension are thought to drive cell sorting by controlling cell-cell contact formation. Here, we show that cell adhesion and cortex tension have different mechanical functions in controlling progenitor cell-cell contact formation and sorting during zebrafish gastrulation. Cortex tension controls cell-cell contact expansion by modulating interfacial tension at the contact. By contrast, adhesion has little direct function in contact expansion, but instead is needed to mechanically couple the cortices of adhering cells at their contacts, allowing cortex tension to control contact expansion. The coupling function of adhesion is mediated by E-cadherin and limited by the mechanical anchoring of E-cadherin to the cortex. Thus, cell adhesion provides the mechanical scaffold for cell cortex tension to drive cell sorting during gastrulation.}, author = {Maître, Jean-Léon and Berthoumieux, Hélène and Krens, Gabriel and Salbreux, Guillaume and Julicher, Frank and Paluch, Ewa and Heisenberg, Carl-Philipp J}, journal = {Science}, number = {6104}, pages = {253 -- 256}, publisher = {American Association for the Advancement of Science}, title = {{Adhesion functions in cell sorting by mechanically coupling the cortices of adhering cells}}, doi = {10.1126/science.1225399}, volume = {338}, year = {2012}, } @article{2952, abstract = {Body axis elongation represents a common and fundamental morphogenetic process in development. A key mechanism triggering body axis elongation without additional growth is convergent extension (CE), whereby a tissue undergoes simultaneous narrowing and extension. Both collective cell migration and cell intercalation are thought to drive CE and are used to different degrees in various species as they elongate their body axis. Here, we provide an overview of CE as a general strategy for body axis elongation and discuss conserved and divergent mechanisms underlying CE among different species.}, author = {Tada, Masazumi and Heisenberg, Carl-Philipp J}, journal = {Development}, number = {21}, pages = {3897 -- 3904}, publisher = {Company of Biologists}, title = {{Convergent extension Using collective cell migration and cell intercalation to shape embryos}}, doi = {10.1242/dev.073007}, volume = {139}, year = {2012}, } @article{2953, author = {Heisenberg, Carl-Philipp J and Fässler, Reinhard}, journal = {Current Opinion in Cell Biology}, number = {5}, pages = {559 -- 561}, publisher = {Elsevier}, title = {{Cell-cell adhesion and extracellular matrix diversity counts}}, doi = {10.1016/j.ceb.2012.09.002}, volume = {24}, year = {2012}, } @article{3245, abstract = {How cells orchestrate their behavior during collective migration is a long-standing question. Using magnetic tweezers to apply mechanical stimuli to Xenopus mesendoderm cells, Weber etal. (2012) now reveal, in this issue of Developmental Cell, a cadherin-mediated mechanosensitive response that promotes cell polarization and movement persistence during the collective mesendoderm migration in gastrulation.}, author = {Behrndt, Martin and Heisenberg, Carl-Philipp J}, journal = {Developmental Cell}, number = {1}, pages = {3 -- 4}, publisher = {Cell Press}, title = {{Spurred by resistance mechanosensation in collective migration}}, doi = {10.1016/j.devcel.2011.12.018}, volume = {22}, year = {2012}, } @article{3246, abstract = {Visualizing and analyzing shape changes at various scales, ranging from single molecules to whole organisms, are essential for understanding complex morphogenetic processes, such as early embryonic development. Embryo morphogenesis relies on the interplay between different tissues, the properties of which are again determined by the interaction between their constituent cells. Cell interactions, on the other hand, are controlled by various molecules, such as signaling and adhesion molecules, which in order to exert their functions need to be spatiotemporally organized within and between the interacting cells. In this review, we will focus on the role of cell adhesion functioning at different scales to organize cell, tissue and embryo morphogenesis. We will specifically ask how the subcellular distribution of adhesion molecules controls the formation of cell-cell contacts, how cell-cell contacts determine tissue shape, and how tissue interactions regulate embryo morphogenesis.}, author = {Barone, Vanessa and Heisenberg, Carl-Philipp J}, journal = {Current Opinion in Cell Biology}, number = {1}, pages = {148 -- 153}, publisher = {Elsevier}, title = {{Cell adhesion in embryo morphogenesis}}, doi = {10.1016/j.ceb.2011.11.006}, volume = {24}, year = {2012}, } @article{3288, abstract = {The zonula adherens (ZA) of epithelial cells is a site of cell-cell adhesion where cellular forces are exerted and resisted. Increasing evidence indicates that E-cadherin adhesion molecules at the ZA serve to sense force applied on the junctions and coordinate cytoskeletal responses to those forces. Efforts to understand the role that cadherins play in mechanotransduction have been limited by the lack of assays to measure the impact of forces on the ZA. In this study we used 4D imaging of GFP-tagged E-cadherin to analyse the movement of the ZA. Junctions in confluent epithelial monolayers displayed prominent movements oriented orthogonal (perpendicular) to the ZA itself. Two components were identified in these movements: a relatively slow unidirectional (translational) component that could be readily fitted by least-squares regression analysis, upon which were superimposed more rapid oscillatory movements. Myosin IIB was a dominant factor responsible for driving the unilateral translational movements. In contrast, frequency spectrum analysis revealed that depletion of Myosin IIA increased the power of the oscillatory movements. This implies that Myosin IIA may serve to dampen oscillatory movements of the ZA. This extends our recent analysis of Myosin II at the ZA to demonstrate that Myosin IIA and Myosin IIB make distinct contributions to junctional movement at the ZA.}, author = {Smutny, Michael and Wu, Selwin and Gomez, Guillermo and Mangold, Sabine and Yap, Alpha and Hamilton, Nicholas}, journal = {PLoS One}, number = {7}, publisher = {Public Library of Science}, title = {{Multicomponent analysis of junctional movements regulated by Myosin II isoforms at the epithelial zonula adherens}}, doi = {10.1371/journal.pone.0022458}, volume = {6}, year = {2011}, } @article{3287, abstract = {Diffusing membrane constituents are constantly exposed to a variety of forces that influence their stochastic path. Single molecule experiments allow for resolving trajectories at extremely high spatial and temporal accuracy, thereby offering insights into en route interactions of the tracer. In this review we discuss approaches to derive information about the underlying processes, based on single molecule tracking experiments. In particular, we focus on a new versatile way to analyze single molecule diffusion in the absence of a full analytical treatment. The method is based on comprehensive comparison of an experimental data set against the hypothetical outcome of multiple experiments performed on the computer. Since Monte Carlo simulations can be easily and rapidly performed even on state-of-the-art PCs, our method provides a simple way for testing various - even complicated - diffusion models. We describe the new method in detail, and show the applicability on two specific examples: firstly, kinetic rate constants can be derived for the transient interaction of mobile membrane proteins; secondly, residence time and corral size can be extracted for confined diffusion.}, author = {Ruprecht, Verena and Axmann, Markus and Wieser, Stefan and Schuetz, Gerhard}, journal = {Current Protein & Peptide Science}, number = {8}, pages = {714 -- 724}, publisher = {Bentham Science Publishers}, title = {{What can we learn from single molecule trajectories?}}, doi = {10.2174/138920311798841753}, volume = {12}, year = {2011}, } @article{3368, abstract = {Tissue surface tension (TST) is an important mechanical property influencing cell sorting and tissue envelopment. The study by Manning et al. (1) reported on a mathematical model describing TST on the basis of the balance between adhesive and tensile properties of the constituent cells. The model predicts that, in high-adhesion cell aggregates, surface cells will be stretched to maintain the same area of cell–cell contact as interior bulk cells, resulting in an elongated and flattened cell shape. The authors (1) observed flat and elongated cells at the surface of high-adhesion zebrafish germ-layer explants, which they argue are undifferentiated stretched germ-layer progenitor cells, and they use this observation as a validation of their model.}, author = {Krens, Gabriel and Möllmert, Stephanie and Heisenberg, Carl-Philipp J}, journal = {PNAS}, number = {3}, pages = {E9 -- E10}, publisher = {National Academy of Sciences}, title = {{Enveloping cell layer differentiation at the surface of zebrafish germ layer tissue explants}}, doi = {10.1073/pnas.1010767108}, volume = {108}, year = {2011}, } @article{3396, abstract = {Facial branchiomotor neurons (FBMNs) in zebrafish and mouse embryonic hindbrain undergo a characteristic tangential migration from rhombomere (r) 4, where they are born, to r6/7. Cohesion among neuroepithelial cells (NCs) has been suggested to function in FBMN migration by inhibiting FBMNs positioned in the basal neuroepithelium such that they move apically between NCs towards the midline of the neuroepithelium instead of tangentially along the basal side of the neuroepithelium towards r6/7. However, direct experimental evaluation of this hypothesis is still lacking. Here, we have used a combination of biophysical cell adhesion measurements and high-resolution time-lapse microscopy to determine the role of NC cohesion in FBMN migration. We show that reducing NC cohesion by interfering with Cadherin 2 (Cdh2) activity results in FBMNs positioned at the basal side of the neuroepithelium moving apically towards the neural tube midline instead of tangentially towards r6/7. In embryos with strongly reduced NC cohesion, ectopic apical FBMN movement frequently results in fusion of the bilateral FBMN clusters over the apical midline of the neural tube. By contrast, reducing cohesion among FBMNs by interfering with Contactin 2 (Cntn2) expression in these cells has little effect on apical FBMN movement, but reduces the fusion of the bilateral FBMN clusters in embryos with strongly diminished NC cohesion. These data provide direct experimental evidence that NC cohesion functions in tangential FBMN migration by restricting their apical movement.}, author = {Stockinger, Petra and Heisenberg, Carl-Philipp J and Maître, Jean-Léon}, journal = {Development}, number = {21}, pages = {4673 -- 4683}, publisher = {Company of Biologists}, title = {{Defective neuroepithelial cell cohesion affects tangential branchiomotor neuron migration in the zebrafish neural tube}}, doi = {10.1242/dev.071233}, volume = {138}, year = {2011}, } @article{3397, abstract = {Recent advances in microscopy techniques and biophysical measurements have provided novel insight into the molecular, cellular and biophysical basis of cell adhesion. However, comparably little is known about a core element of cell–cell adhesion—the energy of adhesion at the cell–cell contact. In this review, we discuss approaches to understand the nature and regulation of adhesion energy, and propose strategies to determine adhesion energy between cells in vitro and in vivo.}, author = {Maître, Jean-Léon and Heisenberg, Carl-Philipp J}, journal = {Current Opinion in Cell Biology}, number = {5}, pages = {508 -- 514}, publisher = {Elsevier}, title = {{The role of adhesion energy in controlling cell-cell contacts}}, doi = {10.1016/j.ceb.2011.07.004}, volume = {23}, year = {2011}, } @article{3379, abstract = {The process of gastrulation is highly conserved across vertebrates on both the genetic and morphological levels, despite great variety in embryonic shape and speed of development. This mechanism spatially separates the germ layers and establishes the organizational foundation for future development. Mesodermal identity is specified in a superficial layer of cells, the epiblast, where cells maintain an epithelioid morphology. These cells involute to join the deeper hypoblast layer where they adopt a migratory, mesenchymal morphology. Expression of a cascade of related transcription factors orchestrates the parallel genetic transition from primitive to mature mesoderm. Although the early and late stages of this process are increasingly well understood, the transition between them has remained largely mysterious. We present here the first high resolution in vivo observations of the blebby transitional morphology of involuting mesodermal cells in a vertebrate embryo. We further demonstrate that the zebrafish spadetail mutation creates a reversible block in the maturation program, stalling cells in the transition state. This mutation creates an ideal system for dissecting the specific properties of cells undergoing the morphological transition of maturing mesoderm, as we demonstrate with a direct measurement of cell–cell adhesion.}, author = {Row, Richard and Maître, Jean-Léon and Martin, Benjamin and Stockinger, Petra and Heisenberg, Carl-Philipp J and Kimelman, David}, journal = {Developmental Biology}, number = {1}, pages = {102 -- 110}, publisher = {Elsevier}, title = {{Completion of the epithelial to mesenchymal transition in zebrafish mesoderm requires Spadetail}}, doi = {10.1016/j.ydbio.2011.03.025}, volume = {354}, year = {2011}, } @article{3383, author = {Heisenberg, Carl-Philipp J}, journal = {FEBS Journal}, number = {S1}, pages = {24 -- 24}, publisher = {Wiley-Blackwell}, title = {{Invited Lectures ‐ Symposia Area}}, doi = {10.1111/j.1742-4658.2011.08136.x}, volume = {278}, year = {2011}, } @inbook{3791, abstract = {During the development of multicellular organisms, cell fate specification is followed by the sorting of different cell types into distinct domains from where the different tissues and organs are formed. Cell sorting involves both the segregation of a mixed population of cells with different fates and properties into distinct domains, and the active maintenance of their segregated state. Because of its biological importance and apparent resemblance to fluid segregation in physics, cell sorting was extensively studied by both biologists and physicists over the last decades. Different theories were developed that try to explain cell sorting on the basis of the physical properties of the constituent cells. However, only recently the molecular and cellular mechanisms that control the physical properties driving cell sorting, have begun to be unraveled. In this review, we will provide an overview of different cell-sorting processes in development and discuss how these processes can be explained by the different sorting theories, and how these theories in turn can be connected to the molecular and cellular mechanisms driving these processes.}, author = {Krens, Gabriel and Heisenberg, Carl-Philipp J}, booktitle = {Forces and Tension in Development}, editor = {Labouesse, Michel}, pages = {189 -- 213}, publisher = {Elsevier}, title = {{Cell sorting in development}}, doi = {10.1016/B978-0-12-385065-2.00006-2}, volume = {95}, year = {2011}, } @phdthesis{3273, author = {Maître, Jean-Léon}, issn = {2663-337X}, publisher = {Institute of Science and Technology Austria}, title = {{Mechanics of adhesion and de‐adhesion in zebrafish germ layer progenitors}}, year = {2011}, }