title: Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis.
abstract: Despite the critical role of endothelial Wnt/β-catenin signaling during central nervous system (CNS) vascularization, how endothelial cells sense and respond to specific Wnt ligands and what aspects of the multistep process of intra-cerebral blood vessel morphogenesis are controlled by these angiogenic signals remain poorly understood. We addressed these questions at single-cell resolution in zebrafish embryos. We identify the GPI-anchored MMP inhibitor Reck and the adhesion GPCR Gpr124 as integral components of a Wnt7a/Wnt7b-specific signaling complex required for brain angiogenesis and dorsal root ganglia neurogenesis. We further show that this atypical Wnt/β-catenin signaling pathway selectively controls endothelial tip cell function and hence, that mosaic restoration of single wild-type tip cells in Wnt/β-catenin-deficient perineural vessels is sufficient to initiate the formation of CNS vessels. Our results identify molecular determinants of ligand specificity of Wnt/β-catenin signaling and provide evidence for organ-specific control of vascular invasion through tight modulation of tip cell function.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
authors.forename: Benoit
authors.initials: B
authors.lastname: Vanhollebeke
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Stone
authors.affiliation: Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Naguissa
authors.initials: N
authors.lastname: Bostaille
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Cho
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
authors.forename: Emilie
authors.initials: E
authors.lastname: Maquet
authors.affiliation: Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Gauquier
authors.affiliation: Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Pauline
authors.initials: P
authors.lastname: Cabochette
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
authors.forename: Didier Yr
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000098:blood supply* / Q000196:embryology; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000502:physiology; D017403:In Situ Hybridization; D008156:Luciferases; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D009024:Morphogenesis / Q000502:physiology*; D016296:Mutagenesis; D018919:Neovascularization, Physiologic / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D059010:Single-Cell Analysis; D059008:Time-Lapse Imaging; D060449:Wnt Signaling Pathway / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D058851:GPI-Linked Proteins; C000605632:RECK protein, zebrafish; D043562:Receptors, G-Protein-Coupled; D029961:Zebrafish Proteins; C000605631:adgra2 protein, zebrafish; D008156:Luciferases
keywords: Gpr124; Reck; Wnt7a/Wnt7b; angiogenesis; brain vascular development; developmental biology; stem cells; tip cell; zebrafish