Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis

Elife. 2015 Jun 8:4:e06489. doi: 10.7554/eLife.06489.


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.

Keywords: Gpr124; Reck; Wnt7a/Wnt7b; angiogenesis; brain vascular development; developmental biology; stem cells; tip cell; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Brain / blood supply*
  • Brain / embryology
  • DNA Primers / genetics
  • Fluorescent Antibody Technique
  • GPI-Linked Proteins / metabolism*
  • Ganglia, Spinal / physiology
  • In Situ Hybridization
  • Luciferases
  • Microarray Analysis
  • Microscopy, Confocal
  • Morphogenesis / physiology*
  • Mutagenesis
  • Neovascularization, Physiologic / physiology*
  • Neurogenesis / physiology
  • Polymerase Chain Reaction
  • Receptors, G-Protein-Coupled / metabolism*
  • Single-Cell Analysis
  • Time-Lapse Imaging
  • Wnt Signaling Pathway / physiology*
  • Zebrafish / embryology*
  • Zebrafish Proteins / metabolism*


  • DNA Primers
  • GPI-Linked Proteins
  • RECK protein, zebrafish
  • Receptors, G-Protein-Coupled
  • Zebrafish Proteins
  • adgra2 protein, zebrafish
  • Luciferases