@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}, }