GPR124 IS A NOVEL CO-ACTIVATOR OF CANONICAL WNT SIGNALING
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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, and endothelial-specific deletion of Gpr124 in mice leads to CNS hypovascularization and a compromised blood-brain barrier (BBB). In the retina, loss of the glia-derived ligand Norrin or its endothelial receptor Frizzled4 (Fz4) causes similar vascular defects. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that: (1) Gpr124 functions as a coactivator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling, (2) Norrin/Fz4 signaling acts predominantly or exclusively through β-catenin (the intracellular effector of canonical Wnt signaling)–dependent transcriptional regulation, and (3) Gpr124-stimulated signaling functions in concert with Norrin/Fz4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific coactivator of canonical Wnt signaling.