Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling

Dev Cell. 2014 Oct 27;31(2):248-56. doi: 10.1016/j.devcel.2014.08.018. Epub 2014 Oct 16.


Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a coactivator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp coreceptor and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific coactivator of canonical Wnt signaling.

Publication types

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

MeSH terms

  • Animals
  • Blood-Brain Barrier / physiology*
  • Cell Line
  • Central Nervous System / blood supply*
  • Central Nervous System / embryology
  • Endothelial Cells / metabolism
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Frizzled Receptors / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-5 / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Neovascularization, Physiologic / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway*


  • Eye Proteins
  • Frizzled Receptors
  • Fzd4 protein, mouse
  • GPR124 protein, mouse
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Lrp5 protein, mouse
  • Ndph protein, mouse
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Wnt Proteins
  • Wnt7a protein, mouse
  • Wnt7b protein, mouse

Associated data

  • GEO/GSE60529
  • GEO/GSM1481718