Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling.
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.
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yulian
Y
Zhou
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jnathans@jhmi.edu.
Jeremy
J
Nathans
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002460:Cell Line; D002490:Central Nervous System / Q000098:blood supply* / Q000196:embryology; D042783:Endothelial Cells / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D051157:Frizzled Receptors / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
D005136:Eye Proteins; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; C554106:GPR124 protein, mouse; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; C095937:Wnt7b protein, mouse