title: Asymmetric division coordinates collective cell migration in angiogenesis.
abstract: The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell division generates daughters of distinct size with discrete 'tip' or 'stalk' thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives Dll4/Notch-independent self-organization of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomizes daughter tip/stalk selection. Thus, asymmetric division seamlessly integrates cell proliferation with collective migration, and, as such, may facilitate growth of other collectively migrating tissues during development, regeneration and cancer invasion.
authors.affiliation: Faculty of Biology, Medicine and Health, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Costa
authors.affiliation: Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Kyle I
authors.initials: KI
authors.lastname: Harrington
authors.affiliation: Faculty of Biology, Medicine and Health, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Lovegrove
authors.affiliation: Faculty of Biology, Medicine and Health, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Page
authors.affiliation: Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chakravartula
authors.affiliation: Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Immunology, Genetics and Pathology Department, University of Uppsala, 751 85 Uppsala, Sweden.
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.affiliation: Faculty of Biology, Medicine and Health, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Shane P
authors.initials: SP
authors.lastname: Herbert
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division; D002465:Cell Movement; D016764:Cell Polarity; D048429:Cell Size; D003198:Computer Simulation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008938:Mitosis; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D059008:Time-Lapse Imaging; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D051880:Receptors, Notch; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D040262:Receptors, Vascular Endothelial Growth Factor