101. Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis.
- Author
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Vanhollebeke B, Stone OA, Bostaille N, Cho C, Zhou Y, Maquet E, Gauquier A, Cabochette P, Fukuhara S, Mochizuki N, Nathans J, and Stainier DY
- Subjects
- Analysis of Variance, Animals, Animals, Genetically Modified, Brain embryology, DNA Primers genetics, Fluorescent Antibody Technique, Ganglia, Spinal physiology, In Situ Hybridization, Luciferases, Microarray Analysis, Microscopy, Confocal, Mutagenesis, Neurogenesis physiology, Polymerase Chain Reaction, Single-Cell Analysis, Time-Lapse Imaging, Brain blood supply, GPI-Linked Proteins metabolism, Morphogenesis physiology, Neovascularization, Physiologic physiology, Receptors, G-Protein-Coupled metabolism, Wnt Signaling Pathway physiology, Zebrafish embryology, Zebrafish Proteins metabolism
- 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.
- Published
- 2015
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