title: Flamingo regulates epiboly and convergence/extension movements through cell cohesive and signalling functions during zebrafish gastrulation.
abstract: During vertebrate gastrulation, the body axis is established by coordinated and directional movements of cells that include epiboly, involution, and convergence and extension (C&E). Recent work implicates a non-canonical Wnt/planar cell polarity (PCP) pathway in the regulation of C&E. The Drosophila atypical cadherin Flamingo (Fmi) and its vertebrate homologue Celsr, a 7-pass transmembrane protein with extracellular cadherin repeats, regulate several biological processes, including C&E, cochlear cell orientation, axonal pathfinding and neuronal migration. Fmi/Celsr can function together with molecules involved in PCP, such as Frizzled (Fz) and Dishevelled (Dsh), but there is also some evidence that it may act as a cell adhesion molecule in a PCP-pathway-independent manner. We show that abrogation of Celsr activity in zebrafish embryos results in epiboly defects that appear to be independent of the requirement for Celsr in PCP signalling during C&E. Using a C-terminal truncated form of Celsr that inhibits membrane presentation of wild-type Celsr through its putative pro-region, a hanging drop assay reveals that cells from embryos with compromised Celsr activity have different cohesive properties from wild-type cells. It is disruption of this ability of Celsr to affect cell cohesion that primarily leads to the in vivo epiboly defects. In addition, Lyn-Celsr, in which the intracellular domain of Celsr is fused to a membrane localisation signal (Lyn), inhibits Fz-Dsh complex formation during Wnt/PCP signalling without affecting epiboly. Fmi/Celsr therefore has a dual role in mediating two separate morphogenetic movements through its roles in mediating cell cohesion and Wnt/PCP signalling during zebrafish gastrulation.
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Filipa
authors.initials: F
authors.lastname: Carreira-Barbosa
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kajita
authors.forename: Mihiko
authors.initials: M
authors.lastname: Kajita
authors.forename: Veronique
authors.initials: V
authors.lastname: Morel
authors.forename: Hironori
authors.initials: H
authors.lastname: Wada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martinez Arias
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujita
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wilson
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000502:physiology; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D004625:Embryo, Nonmammalian / Q000502:physiology; D051157:Frizzled Receptors / Q000378:metabolism; D054262:Gastrulation / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D055503:Protein Multimerization; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D029961:Zebrafish Proteins; C502947:celsr1a protein, zebrafish; C502948:celsr1b protein, zebrafish; C000606588:dsh protein, Drosophila; C503354:fzd8a protein, zebrafish; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases