title: Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.
abstract: Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Junlei
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Mancuso
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Maier
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Xibin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Kanako
authors.initials: K
authors.lastname: Yuki
authors.affiliation: Department of Molecular and Cellular Biology and Integrative Genomics Core, City of Hope, Duarte, California, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Kwong
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Rao
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Vallon
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kosinski
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: J J Haijing
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Mah
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Gholamin
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Reyes
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Kuhnert
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Shin-Heng
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ari D
authors.initials: AD
authors.lastname: Brettman
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Daly
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Corney
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Cheshier
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Linda D
authors.initials: LD
authors.lastname: Shortliffe
authors.affiliation: Department of Molecular and Cellular Biology and Integrative Genomics Core, City of Hope, Duarte, California, USA.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Pak
authors.initials: P
authors.lastname: Chan
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Rona G
authors.initials: RG
authors.lastname: Giffard
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.|Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Andreasson
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics* / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D055806:Microvessels; D020286:Pericytes / Q000648:ultrastructure; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D060449:Wnt Signaling Pathway
chemical_list: C554106:GPR124 protein, mouse; D043562:Receptors, G-Protein-Coupled