[{"department":[{"_id":"MiSi"},{"_id":"EM-Fac"},{"_id":"NanoFab"},{"_id":"BjHo"}],"date_updated":"2024-03-27T23:30:23Z","ddc":["570"],"tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"article_type":"original","type":"journal_article","status":"public","_id":"10703","ec_funded":1,"related_material":{"record":[{"relation":"dissertation_contains","id":"12726","status":"public"},{"relation":"dissertation_contains","status":"public","id":"14530"},{"status":"public","id":"12401","relation":"dissertation_contains"}]},"issue":"1","volume":57,"publication_status":"published","publication_identifier":{"issn":["1534-5807"],"eissn":["1878-1551"]},"language":[{"iso":"eng"}],"main_file_link":[{"url":"https://www.sciencedirect.com/science/article/pii/S1534580721009497","open_access":"1"}],"scopus_import":"1","intvolume":" 57","month":"01","abstract":[{"text":"When crawling through the body, leukocytes often traverse tissues that are densely packed with extracellular matrix and other cells, and this raises the question: How do leukocytes overcome compressive mechanical loads? Here, we show that the actin cortex of leukocytes is mechanoresponsive and that this responsiveness requires neither force sensing via the nucleus nor adhesive interactions with a substrate. Upon global compression of the cell body as well as local indentation of the plasma membrane, Wiskott-Aldrich syndrome protein (WASp) assembles into dot-like structures, providing activation platforms for Arp2/3 nucleated actin patches. These patches locally push against the external load, which can be obstructing collagen fibers or other cells, and thereby create space to facilitate forward locomotion. We show in vitro and in vivo that this WASp function is rate limiting for ameboid leukocyte migration in dense but not in loose environments and is required for trafficking through diverse tissues such as skin and lymph nodes.","lang":"eng"}],"acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"Bio"},{"_id":"EM-Fac"}],"pmid":1,"oa_version":"Published Version","article_processing_charge":"No","external_id":{"isi":["000768933800005"],"pmid":["34919802"]},"author":[{"full_name":"Gaertner, Florian","last_name":"Gaertner","first_name":"Florian"},{"last_name":"Reis-Rodrigues","full_name":"Reis-Rodrigues, Patricia","first_name":"Patricia"},{"first_name":"Ingrid","id":"4C7D837E-F248-11E8-B48F-1D18A9856A87","full_name":"De Vries, Ingrid","last_name":"De Vries"},{"full_name":"Hons, Miroslav","orcid":"0000-0002-6625-3348","last_name":"Hons","first_name":"Miroslav","id":"4167FE56-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Juan","last_name":"Aguilera","full_name":"Aguilera, Juan"},{"orcid":"0000-0003-4844-6311","full_name":"Riedl, Michael","last_name":"Riedl","first_name":"Michael","id":"3BE60946-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Alexander F","id":"3B1B77E4-F248-11E8-B48F-1D18A9856A87","last_name":"Leithner","orcid":"0000-0002-1073-744X","full_name":"Leithner, Alexander F"},{"full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X","last_name":"Tasciyan","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren"},{"id":"31DAC7B6-F248-11E8-B48F-1D18A9856A87","first_name":"Aglaja","last_name":"Kopf","orcid":"0000-0002-2187-6656","full_name":"Kopf, Aglaja"},{"id":"4515C308-F248-11E8-B48F-1D18A9856A87","first_name":"Jack","last_name":"Merrin","full_name":"Merrin, Jack","orcid":"0000-0001-5145-4609"},{"id":"39C5A68A-F248-11E8-B48F-1D18A9856A87","first_name":"Vanessa","last_name":"Zheden","full_name":"Zheden, Vanessa","orcid":"0000-0002-9438-4783"},{"full_name":"Kaufmann, Walter","orcid":"0000-0001-9735-5315","last_name":"Kaufmann","id":"3F99E422-F248-11E8-B48F-1D18A9856A87","first_name":"Walter"},{"id":"4E01D6B4-F248-11E8-B48F-1D18A9856A87","first_name":"Robert","last_name":"Hauschild","orcid":"0000-0001-9843-3522","full_name":"Hauschild, Robert"},{"orcid":"0000-0002-6620-9179","full_name":"Sixt, Michael K","last_name":"Sixt","first_name":"Michael K","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87"}],"title":"WASp triggers mechanosensitive actin patches to facilitate immune cell migration in dense tissues","citation":{"short":"F. Gaertner, P. Reis-Rodrigues, I. de Vries, M. Hons, J. Aguilera, M. Riedl, A.F. Leithner, S. Tasciyan, A. Kopf, J. Merrin, V. Zheden, W. Kaufmann, R. Hauschild, M.K. Sixt, Developmental Cell 57 (2022) 47–62.e9.","ieee":"F. Gaertner et al., “WASp triggers mechanosensitive actin patches to facilitate immune cell migration in dense tissues,” Developmental Cell, vol. 57, no. 1. Cell Press ; Elsevier, p. 47–62.e9, 2022.","apa":"Gaertner, F., Reis-Rodrigues, P., de Vries, I., Hons, M., Aguilera, J., Riedl, M., … Sixt, M. K. (2022). WASp triggers mechanosensitive actin patches to facilitate immune cell migration in dense tissues. Developmental Cell. Cell Press ; Elsevier. https://doi.org/10.1016/j.devcel.2021.11.024","ama":"Gaertner F, Reis-Rodrigues P, de Vries I, et al. WASp triggers mechanosensitive actin patches to facilitate immune cell migration in dense tissues. Developmental Cell. 2022;57(1):47-62.e9. doi:10.1016/j.devcel.2021.11.024","mla":"Gaertner, Florian, et al. “WASp Triggers Mechanosensitive Actin Patches to Facilitate Immune Cell Migration in Dense Tissues.” Developmental Cell, vol. 57, no. 1, Cell Press ; Elsevier, 2022, p. 47–62.e9, doi:10.1016/j.devcel.2021.11.024.","ista":"Gaertner F, Reis-Rodrigues P, de Vries I, Hons M, Aguilera J, Riedl M, Leithner AF, Tasciyan S, Kopf A, Merrin J, Zheden V, Kaufmann W, Hauschild R, Sixt MK. 2022. WASp triggers mechanosensitive actin patches to facilitate immune cell migration in dense tissues. Developmental Cell. 57(1), 47–62.e9.","chicago":"Gaertner, Florian, Patricia Reis-Rodrigues, Ingrid de Vries, Miroslav Hons, Juan Aguilera, Michael Riedl, Alexander F Leithner, et al. “WASp Triggers Mechanosensitive Actin Patches to Facilitate Immune Cell Migration in Dense Tissues.” Developmental Cell. Cell Press ; Elsevier, 2022. https://doi.org/10.1016/j.devcel.2021.11.024."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","project":[{"grant_number":"747687","name":"Mechanical Adaptation of Lamellipodial Actin Networks in Migrating Cells","_id":"260AA4E2-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"grant_number":"724373","name":"Cellular navigation along spatial gradients","call_identifier":"H2020","_id":"25FE9508-B435-11E9-9278-68D0E5697425"}],"page":"47-62.e9","date_created":"2022-01-30T23:01:33Z","date_published":"2022-01-10T00:00:00Z","doi":"10.1016/j.devcel.2021.11.024","year":"2022","isi":1,"publication":"Developmental Cell","day":"10","oa":1,"quality_controlled":"1","publisher":"Cell Press ; Elsevier","acknowledgement":"We thank N. Darwish-Miranda, F. Leite, F.P. Assen, and A. Eichner for advice and help with experiments. We thank J. Renkawitz, E. Kiermaier, A. Juanes Garcia, and M. Avellaneda for critical reading of the manuscript. We thank M. Driscoll for advice on fluorescent labeling of collagen gels. This research was supported by the Scientific Service Units (SSUs) of IST Austria through resources provided by Molecular Biology Services/Lab Support Facility (LSF)/Bioimaging Facility/Electron Microscopy Facility. This work was funded by grants from the European Research Council ( CoG 724373 ) and the Austrian Science Foundation (FWF) to M.S. F.G. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 747687."},{"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","citation":{"apa":"Tasciyan, S. (2022). Role of microenvironment heterogeneity in cancer cell invasion. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:12401","ama":"Tasciyan S. Role of microenvironment heterogeneity in cancer cell invasion. 2022. doi:10.15479/at:ista:12401","short":"S. Tasciyan, Role of Microenvironment Heterogeneity in Cancer Cell Invasion, Institute of Science and Technology Austria, 2022.","ieee":"S. Tasciyan, “Role of microenvironment heterogeneity in cancer cell invasion,” Institute of Science and Technology Austria, 2022.","mla":"Tasciyan, Saren. Role of Microenvironment Heterogeneity in Cancer Cell Invasion. Institute of Science and Technology Austria, 2022, doi:10.15479/at:ista:12401.","ista":"Tasciyan S. 2022. Role of microenvironment heterogeneity in cancer cell invasion. Institute of Science and Technology Austria.","chicago":"Tasciyan, Saren. “Role of Microenvironment Heterogeneity in Cancer Cell Invasion.” Institute of Science and Technology Austria, 2022. https://doi.org/10.15479/at:ista:12401."},"title":"Role of microenvironment heterogeneity in cancer cell invasion","article_processing_charge":"No","author":[{"first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","last_name":"Tasciyan","orcid":"0000-0003-1671-393X","full_name":"Tasciyan, Saren"}],"oa":1,"publisher":"Institute of Science and Technology Austria","day":"22","year":"2022","has_accepted_license":"1","date_created":"2023-01-26T11:55:16Z","date_published":"2022-12-22T00:00:00Z","doi":"10.15479/at:ista:12401","page":"105","_id":"12401","status":"public","type":"dissertation","ddc":["610"],"date_updated":"2023-12-21T23:30:04Z","supervisor":[{"orcid":"0000-0002-6620-9179","full_name":"Sixt, Michael K","last_name":"Sixt","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","first_name":"Michael K"}],"department":[{"_id":"GradSch"},{"_id":"MiSi"}],"file_date_updated":"2023-12-21T23:30:03Z","oa_version":"Published Version","abstract":[{"text":"Detachment of the cancer cells from the bulk of the tumor is the first step of metastasis, which\r\nis the primary cause of cancer related deaths. It is unclear, which factors contribute to this step.\r\nRecent studies indicate a crucial role of the tumor microenvironment in malignant\r\ntransformation and metastasis. Studying cancer cell invasion and detachments quantitatively in\r\nthe context of its physiological microenvironment is technically challenging. Especially, precise\r\ncontrol of microenvironmental properties in vivo is currently not possible. Here, I studied the\r\nrole of microenvironment geometry in the invasion and detachment of cancer cells from the\r\nbulk with a simplistic and reductionist approach. In this approach, I engineered microfluidic\r\ndevices to mimic a pseudo 3D extracellular matrix environment, where I was able to\r\nquantitatively tune the geometrical configuration of the microenvironment and follow tumor\r\ncells with fluorescence live imaging. To aid quantitative analysis I developed a widely applicable\r\nsoftware application to automatically analyze and visualize particle tracking data.\r\nQuantitative analysis of tumor cell invasion in isotropic and anisotropic microenvironments\r\nshowed that heterogeneity in the microenvironment promotes faster invasion and more\r\nfrequent detachment of cells. These observations correlated with overall higher speed of cells at\r\nthe edge of the bulk of the cells. In heterogeneous microenvironments cells preferentially\r\npassed through larger pores, thus invading areas of least resistance and generating finger-like\r\ninvasive structures. The detachments occurred mostly at the tips of these structures.\r\nTo investigate the potential mechanism, we established a two dimensional model to simulate\r\nactive Brownian particles representing the cell nuclei dynamics. These simulations backed our in\r\nvitro observations without the need of precise fitting the simulation parameters. Our model\r\nsuggests the importance of the pore heterogeneity in the direction perpendicular to the\r\norientation of bias field (lateral heterogeneity), which causes the interface roughening.","lang":"eng"}],"month":"12","alternative_title":["ISTA Thesis"],"language":[{"iso":"eng"}],"file":[{"embargo":"2023-12-20","checksum":"cc4a2b4a7e3c4ee8ef7f2dbf909b12bd","file_id":"12402","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_name":"PhD-Thesis_Saren Tasciyan_formatted_aftercrash_fixed_600dpi_95pc_final_PDFA3b.pdf","date_created":"2023-01-26T11:58:14Z","file_size":42059787,"date_updated":"2023-12-21T23:30:03Z","creator":"cchlebak"},{"file_size":261256696,"date_updated":"2023-12-21T23:30:03Z","creator":"cchlebak","file_name":"Source Files - Saren Tasciyan - PhD Thesis.zip","date_created":"2023-01-26T12:00:10Z","embargo_to":"open_access","content_type":"application/x-zip-compressed","relation":"source_file","access_level":"closed","checksum":"f1b4ca98b8ab0cb043b1830971e9bd9c","file_id":"12403"}],"publication_status":"published","degree_awarded":"PhD","publication_identifier":{"issn":["2663-337X"]},"related_material":{"record":[{"relation":"part_of_dissertation","id":"679","status":"public"},{"status":"public","id":"10703","relation":"part_of_dissertation"},{"status":"public","id":"9429","relation":"part_of_dissertation"},{"relation":"part_of_dissertation","status":"public","id":"7885"}]}},{"intvolume":" 12","month":"05","oa_version":"Published Version","acknowledged_ssus":[{"_id":"PreCl"}],"abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.","lang":"eng"}],"ec_funded":1,"issue":"1","volume":12,"related_material":{"link":[{"relation":"press_release","url":"https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/"}],"record":[{"relation":"earlier_version","id":"7800","status":"public"},{"relation":"dissertation_contains","id":"12401","status":"public"}]},"language":[{"iso":"eng"}],"file":[{"date_updated":"2021-05-28T12:39:43Z","file_size":9358599,"creator":"kschuh","date_created":"2021-05-28T12:39:43Z","file_name":"2021_NatureCommunications_Morandell.pdf","content_type":"application/pdf","access_level":"open_access","relation":"main_file","file_id":"9430","checksum":"337e0f7959c35ec959984cacdcb472ba","success":1}],"publication_status":"published","publication_identifier":{"eissn":["2041-1723"]},"keyword":["General Biochemistry","Genetics and Molecular Biology"],"status":"public","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_type":"original","type":"journal_article","_id":"9429","file_date_updated":"2021-05-28T12:39:43Z","department":[{"_id":"GaNo"},{"_id":"JoDa"},{"_id":"FlSc"},{"_id":"MiSi"},{"_id":"LifeSc"},{"_id":"Bio"}],"ddc":["572"],"date_updated":"2024-03-27T23:30:23Z","oa":1,"quality_controlled":"1","publisher":"Springer Nature","acknowledgement":"We thank A. Coll Manzano, F. Freeman, M. Ladron de Guevara, and A. Ç. Yahya for technical assistance, S. Deixler, A. Lepold, and A. Schlerka for the management of our animal colony, as well as M. Schunn and the Preclinical Facility team for technical assistance. We thank K. Heesom and her team at the University of Bristol Proteomics Facility for the proteomics sample preparation, data generation, and analysis support. We thank Y. B. Simon for kindly providing the plasmid for lentiviral labeling. Further, we thank M. Sixt for his advice regarding cell migration and the fruitful discussions. This work was supported by the ISTPlus postdoctoral fellowship (Grant Agreement No. 754411) to B.B., by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM), and by the Austrian Science Fund (FWF) to G.N. (DK W1232-B24 and SFB F7807-B) and to J.G.D (I3600-B27).","date_created":"2021-05-28T11:49:46Z","doi":"10.1038/s41467-021-23123-x","date_published":"2021-05-24T00:00:00Z","publication":"Nature Communications","day":"24","year":"2021","isi":1,"has_accepted_license":"1","project":[{"name":"ISTplus - Postdoctoral Fellowships","grant_number":"754411","call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425"},{"call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425","grant_number":"715508","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425"},{"name":"Neural stem cells in autism and epilepsy","grant_number":"F07807","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E"},{"call_identifier":"FWF","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","grant_number":"I03600","name":"Optical control of synaptic function via adhesion molecules"}],"article_number":"3058","title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","article_processing_charge":"No","external_id":{"isi":["000658769900010"]},"author":[{"full_name":"Morandell, Jasmin","last_name":"Morandell","first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87","full_name":"Schwarz, Lena A","last_name":"Schwarz"},{"full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette"},{"last_name":"Tasciyan","orcid":"0000-0003-1671-393X","full_name":"Tasciyan, Saren","first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Dimchev","full_name":"Dimchev, Georgi A","orcid":"0000-0001-8370-6161","first_name":"Georgi A","id":"38C393BE-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Nicolas, Armel","last_name":"Nicolas","first_name":"Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87"},{"id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph M","full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer"},{"full_name":"Kreuzinger, Caroline","last_name":"Kreuzinger","id":"382077BA-F248-11E8-B48F-1D18A9856A87","first_name":"Caroline"},{"first_name":"Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","last_name":"Dotter","full_name":"Dotter, Christoph","orcid":"0000-0002-9033-9096"},{"last_name":"Knaus","full_name":"Knaus, Lisa","first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87"},{"id":"D23090A2-9057-11EA-883A-A8396FC7A38F","first_name":"Zoe","full_name":"Dobler, Zoe","last_name":"Dobler"},{"last_name":"Cacci","full_name":"Cacci, Emanuele","first_name":"Emanuele"},{"first_name":"Florian KM","id":"48AD8942-F248-11E8-B48F-1D18A9856A87","full_name":"Schur, Florian KM","orcid":"0000-0003-4790-8078","last_name":"Schur"},{"first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973","last_name":"Danzl"},{"full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” Nature Communications, vol. 12, no. 1. Springer Nature, 2021.","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, G.A. Dimchev, A. Nicolas, C.M. Sommer, C. Kreuzinger, C. Dotter, L. Knaus, Z. Dobler, E. Cacci, F.K. Schur, J.G. Danzl, G. Novarino, Nature Communications 12 (2021).","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Dimchev, G. A., Nicolas, A., … Novarino, G. (2021). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-021-23123-x","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 2021;12(1). doi:10.1038/s41467-021-23123-x","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications, vol. 12, no. 1, 3058, Springer Nature, 2021, doi:10.1038/s41467-021-23123-x.","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev GA, Nicolas A, Sommer CM, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur FK, Danzl JG, Novarino G. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 12(1), 3058.","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Georgi A Dimchev, Armel Nicolas, Christoph M Sommer, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-23123-x."}},{"month":"01","oa_version":"Preprint","acknowledged_ssus":[{"_id":"PreCl"}],"abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages.","lang":"eng"}],"related_material":{"record":[{"relation":"later_version","status":"public","id":"9429"},{"relation":"dissertation_contains","id":"8620","status":"public"}]},"file":[{"checksum":"c6799ab5daba80efe8e2ed63c15f8c81","file_id":"7801","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_name":"2020.01.10.902064v1.full.pdf","date_created":"2020-05-05T14:31:19Z","file_size":2931370,"date_updated":"2020-07-14T12:48:03Z","creator":"rsix"}],"language":[{"iso":"eng"}],"publication_status":"submitted","status":"public","type":"preprint","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"_id":"7800","file_date_updated":"2020-07-14T12:48:03Z","department":[{"_id":"JoDa"},{"_id":"GaNo"},{"_id":"LifeSc"}],"ddc":["570"],"date_updated":"2024-03-27T23:30:14Z","publisher":"Cold Spring Harbor Laboratory","oa":1,"doi":"10.1101/2020.01.10.902064 ","date_published":"2020-01-11T00:00:00Z","date_created":"2020-05-05T14:31:33Z","day":"11","publication":"bioRxiv","has_accepted_license":"1","year":"2020","project":[{"call_identifier":"FWF","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","grant_number":"I03600","name":"Optical control of synaptic function via adhesion molecules"},{"name":"Molecular Drug Targets","grant_number":"W1232-B24","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425"}],"title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","author":[{"last_name":"Morandell","full_name":"Morandell, Jasmin","first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87","full_name":"Schwarz, Lena A","last_name":"Schwarz"},{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","last_name":"Basilico","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173"},{"first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","last_name":"Tasciyan","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X"},{"id":"2A103192-F248-11E8-B48F-1D18A9856A87","first_name":"Armel","last_name":"Nicolas","full_name":"Nicolas, Armel"},{"last_name":"Sommer","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Kreuzinger","full_name":"Kreuzinger, Caroline","id":"382077BA-F248-11E8-B48F-1D18A9856A87","first_name":"Caroline"},{"full_name":"Knaus, Lisa","last_name":"Knaus","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","first_name":"Lisa"},{"full_name":"Dobler, Zoe","last_name":"Dobler","first_name":"Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F"},{"first_name":"Emanuele","full_name":"Cacci, Emanuele","last_name":"Cacci"},{"last_name":"Danzl","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G","first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino"}],"article_processing_charge":"No","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv, 10.1101/2020.01.10.902064 .","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2020.01.10.902064 .","ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” bioRxiv. Cold Spring Harbor Laboratory.","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer, C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv (n.d.).","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. doi:10.1101/2020.01.10.902064 ","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer, C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.01.10.902064 ","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2020.01.10.902064 ."}},{"quality_controlled":"1","publisher":"Springer Nature","acknowledgement":"We thank A. Leithner and J. Renkawitz for discussion and critical reading of the manuscript; J. Schwarz and M. Mehling for establishing the microfluidic setups; the Bioimaging Facility of IST Austria for excellent support, as well as the Life Science Facility and the Miba Machine Shop of IST Austria; and F. N. Arslan, L. E. Burnett and L. Li for their work during their rotation in the IST PhD programme. This work was supported by the European Research Council (ERC StG 281556 and CoG 724373) to M.S. and grants from the Austrian Science Fund (FWF P29911) and the WWTF to M.S. M.H. was supported by the European Regional Development Fund Project (CZ.02.1.01/0.0/0.0/15_003/0000476). F.G. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 747687.","date_created":"2020-05-24T22:01:01Z","date_published":"2020-06-25T00:00:00Z","doi":"10.1038/s41586-020-2283-z","page":"582–585","publication":"Nature","day":"25","year":"2020","isi":1,"project":[{"call_identifier":"FP7","_id":"25A603A2-B435-11E9-9278-68D0E5697425","name":"Cytoskeletal force generation and force transduction of migrating leukocytes","grant_number":"281556"},{"call_identifier":"H2020","_id":"25FE9508-B435-11E9-9278-68D0E5697425","grant_number":"724373","name":"Cellular navigation along spatial gradients"},{"name":"Mechanical adaptation of lamellipodial actin","grant_number":"P29911","_id":"26018E70-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"name":"Mechanical Adaptation of Lamellipodial Actin Networks in Migrating Cells","grant_number":"747687","call_identifier":"H2020","_id":"260AA4E2-B435-11E9-9278-68D0E5697425"}],"title":"Cellular locomotion using environmental topography","external_id":{"isi":["000532688300008"]},"article_processing_charge":"No","author":[{"id":"35B76592-F248-11E8-B48F-1D18A9856A87","first_name":"Anne","last_name":"Reversat","orcid":"0000-0003-0666-8928","full_name":"Reversat, Anne"},{"first_name":"Florian R","id":"397A88EE-F248-11E8-B48F-1D18A9856A87","full_name":"Gärtner, Florian R","orcid":"0000-0001-6120-3723","last_name":"Gärtner"},{"first_name":"Jack","id":"4515C308-F248-11E8-B48F-1D18A9856A87","full_name":"Merrin, Jack","orcid":"0000-0001-5145-4609","last_name":"Merrin"},{"full_name":"Stopp, Julian A","last_name":"Stopp","id":"489E3F00-F248-11E8-B48F-1D18A9856A87","first_name":"Julian A"},{"first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X","last_name":"Tasciyan"},{"id":"2A67C376-F248-11E8-B48F-1D18A9856A87","first_name":"Juan L","last_name":"Aguilera Servin","orcid":"0000-0002-2862-8372","full_name":"Aguilera Servin, Juan L"},{"first_name":"Ingrid","id":"4C7D837E-F248-11E8-B48F-1D18A9856A87","full_name":"De Vries, Ingrid","last_name":"De Vries"},{"id":"4E01D6B4-F248-11E8-B48F-1D18A9856A87","first_name":"Robert","orcid":"0000-0001-9843-3522","full_name":"Hauschild, Robert","last_name":"Hauschild"},{"first_name":"Miroslav","id":"4167FE56-F248-11E8-B48F-1D18A9856A87","last_name":"Hons","full_name":"Hons, Miroslav","orcid":"0000-0002-6625-3348"},{"last_name":"Piel","full_name":"Piel, Matthieu","first_name":"Matthieu"},{"first_name":"Andrew","full_name":"Callan-Jones, Andrew","last_name":"Callan-Jones"},{"first_name":"Raphael","last_name":"Voituriez","full_name":"Voituriez, Raphael"},{"last_name":"Sixt","full_name":"Sixt, Michael K","orcid":"0000-0002-6620-9179","first_name":"Michael K","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"ista":"Reversat A, Gärtner FR, Merrin J, Stopp JA, Tasciyan S, Aguilera Servin JL, de Vries I, Hauschild R, Hons M, Piel M, Callan-Jones A, Voituriez R, Sixt MK. 2020. Cellular locomotion using environmental topography. Nature. 582, 582–585.","chicago":"Reversat, Anne, Florian R Gärtner, Jack Merrin, Julian A Stopp, Saren Tasciyan, Juan L Aguilera Servin, Ingrid de Vries, et al. “Cellular Locomotion Using Environmental Topography.” Nature. Springer Nature, 2020. https://doi.org/10.1038/s41586-020-2283-z.","ieee":"A. Reversat et al., “Cellular locomotion using environmental topography,” Nature, vol. 582. Springer Nature, pp. 582–585, 2020.","short":"A. Reversat, F.R. Gärtner, J. Merrin, J.A. Stopp, S. Tasciyan, J.L. Aguilera Servin, I. de Vries, R. Hauschild, M. Hons, M. Piel, A. Callan-Jones, R. Voituriez, M.K. Sixt, Nature 582 (2020) 582–585.","ama":"Reversat A, Gärtner FR, Merrin J, et al. Cellular locomotion using environmental topography. Nature. 2020;582:582–585. doi:10.1038/s41586-020-2283-z","apa":"Reversat, A., Gärtner, F. R., Merrin, J., Stopp, J. A., Tasciyan, S., Aguilera Servin, J. L., … Sixt, M. K. (2020). Cellular locomotion using environmental topography. Nature. Springer Nature. https://doi.org/10.1038/s41586-020-2283-z","mla":"Reversat, Anne, et al. “Cellular Locomotion Using Environmental Topography.” Nature, vol. 582, Springer Nature, 2020, pp. 582–585, doi:10.1038/s41586-020-2283-z."},"intvolume":" 582","month":"06","scopus_import":"1","oa_version":"None","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"M-Shop"}],"abstract":[{"lang":"eng","text":"Eukaryotic cells migrate by coupling the intracellular force of the actin cytoskeleton to the environment. While force coupling is usually mediated by transmembrane adhesion receptors, especially those of the integrin family, amoeboid cells such as leukocytes can migrate extremely fast despite very low adhesive forces1. Here we show that leukocytes cannot only migrate under low adhesion but can also transmit forces in the complete absence of transmembrane force coupling. When confined within three-dimensional environments, they use the topographical features of the substrate to propel themselves. Here the retrograde flow of the actin cytoskeleton follows the texture of the substrate, creating retrograde shear forces that are sufficient to drive the cell body forwards. Notably, adhesion-dependent and adhesion-independent migration are not mutually exclusive, but rather are variants of the same principle of coupling retrograde actin flow to the environment and thus can potentially operate interchangeably and simultaneously. As adhesion-free migration is independent of the chemical composition of the environment, it renders cells completely autonomous in their locomotive behaviour."}],"ec_funded":1,"volume":582,"related_material":{"record":[{"status":"public","id":"14697","relation":"dissertation_contains"},{"id":"12401","status":"public","relation":"dissertation_contains"}],"link":[{"description":"News on IST Homepage","relation":"press_release","url":"https://ist.ac.at/en/news/off-road-mode-enables-mobile-cells-to-move-freely/"}]},"language":[{"iso":"eng"}],"publication_status":"published","publication_identifier":{"issn":["00280836"],"eissn":["14764687"]},"status":"public","article_type":"original","type":"journal_article","_id":"7885","department":[{"_id":"NanoFab"},{"_id":"Bio"},{"_id":"MiSi"}],"date_updated":"2024-03-27T23:30:23Z"},{"year":"2017","publication":"The Journal of Clinical Investigation","day":"01","page":"2051 - 2065","date_created":"2018-12-11T11:47:53Z","date_published":"2017-06-01T00:00:00Z","doi":"10.1172/JCI80631","acknowledgement":"This work was supported by grants from the Austrian Science Fund (FWF) (P27538-B21, I1621-B22, and SFB 43, to PK); by funding from the European Union Seventh Framework Programme Marie Curie Initial Training Networks (FP7-PEOPLE-2012-ITN) for the project INBIONET (INfection BIOlogy Training NETwork under grant agreement PITN-GA-2012-316682; and by a joint research cluster initiative of the University of Vienna and the Medical University of Vienna.","oa":1,"quality_controlled":"1","publisher":"American Society for Clinical Investigation","citation":{"chicago":"Ebner, Florian, Vitaly Sedlyarov, Saren Tasciyan, Masa Ivin, Franz Kratochvill, Nina Gratz, Lukas Kenner, Andreas Villunger, Michael K Sixt, and Pavel Kovarik. “The RNA-Binding Protein Tristetraprolin Schedules Apoptosis of Pathogen-Engaged Neutrophils during Bacterial Infection.” The Journal of Clinical Investigation. American Society for Clinical Investigation, 2017. https://doi.org/10.1172/JCI80631.","ista":"Ebner F, Sedlyarov V, Tasciyan S, Ivin M, Kratochvill F, Gratz N, Kenner L, Villunger A, Sixt MK, Kovarik P. 2017. The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection. The Journal of Clinical Investigation. 127(6), 2051–2065.","mla":"Ebner, Florian, et al. “The RNA-Binding Protein Tristetraprolin Schedules Apoptosis of Pathogen-Engaged Neutrophils during Bacterial Infection.” The Journal of Clinical Investigation, vol. 127, no. 6, American Society for Clinical Investigation, 2017, pp. 2051–65, doi:10.1172/JCI80631.","apa":"Ebner, F., Sedlyarov, V., Tasciyan, S., Ivin, M., Kratochvill, F., Gratz, N., … Kovarik, P. (2017). The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection. The Journal of Clinical Investigation. American Society for Clinical Investigation. https://doi.org/10.1172/JCI80631","ama":"Ebner F, Sedlyarov V, Tasciyan S, et al. The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection. The Journal of Clinical Investigation. 2017;127(6):2051-2065. doi:10.1172/JCI80631","ieee":"F. Ebner et al., “The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection,” The Journal of Clinical Investigation, vol. 127, no. 6. American Society for Clinical Investigation, pp. 2051–2065, 2017.","short":"F. Ebner, V. Sedlyarov, S. Tasciyan, M. Ivin, F. Kratochvill, N. Gratz, L. Kenner, A. Villunger, M.K. Sixt, P. Kovarik, The Journal of Clinical Investigation 127 (2017) 2051–2065."},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","external_id":{"pmid":["28504646"]},"publist_id":"7038","author":[{"first_name":"Florian","full_name":"Ebner, Florian","last_name":"Ebner"},{"full_name":"Sedlyarov, Vitaly","last_name":"Sedlyarov","first_name":"Vitaly"},{"last_name":"Tasciyan","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren"},{"first_name":"Masa","last_name":"Ivin","full_name":"Ivin, Masa"},{"full_name":"Kratochvill, Franz","last_name":"Kratochvill","first_name":"Franz"},{"first_name":"Nina","full_name":"Gratz, Nina","last_name":"Gratz"},{"first_name":"Lukas","last_name":"Kenner","full_name":"Kenner, Lukas"},{"last_name":"Villunger","full_name":"Villunger, Andreas","first_name":"Andreas"},{"first_name":"Michael K","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","last_name":"Sixt","full_name":"Sixt, Michael K","orcid":"0000-0002-6620-9179"},{"full_name":"Kovarik, Pavel","last_name":"Kovarik","first_name":"Pavel"}],"title":"The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection","project":[{"call_identifier":"FWF","_id":"25985A36-B435-11E9-9278-68D0E5697425","name":"The biochemical basis of PAR polarization","grant_number":"T00817-B21"},{"grant_number":"P27201-B22","name":"Revealing the mechanisms underlying drug interactions","_id":"25E9AF9E-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"}],"publication_status":"published","publication_identifier":{"issn":["00219738"]},"language":[{"iso":"eng"}],"volume":127,"issue":"6","related_material":{"record":[{"id":"12401","status":"public","relation":"dissertation_contains"}]},"abstract":[{"text":"Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity. Activated TTP-deficient neutrophils exhibited decreased apoptosis and enhanced accumulation at the infection site. In the context of myeloid-specific deletion of Ttp, the potentiation of neutrophil deployment protected mice against lethal soft tissue infection with Streptococcus pyogenes and prevented bacterial dissemination. Neutrophil transcriptome analysis revealed that decreased apoptosis of TTP-deficient neutrophils was specifically associated with elevated expression of myeloid cell leukemia 1 (Mcl1) but not other antiapoptotic B cell leukemia/ lymphoma 2 (Bcl2) family members. Higher Mcl1 expression resulted from stabilization of Mcl1 mRNA in the absence of TTP. The low apoptosis rate of infiltrating TTP-deficient neutrophils was comparable to that of transgenic Mcl1-overexpressing neutrophils. Our study demonstrates that posttranscriptional gene regulation by TTP schedules the termination of the antimicrobial engagement of neutrophils. The balancing role of TTP comes at the cost of an increased risk of bacterial infections.","lang":"eng"}],"pmid":1,"oa_version":"Submitted Version","main_file_link":[{"open_access":"1","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451238/"}],"scopus_import":1,"intvolume":" 127","month":"06","date_updated":"2024-03-27T23:30:23Z","department":[{"_id":"MiSi"}],"_id":"679","type":"journal_article","status":"public"}]