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Nat Med. 2017 Apr;23(4):450-460. doi: 10.1038/nm.4309. Epub 2017 Mar 13.

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.

Author information

1
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
2
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
3
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
4
Department of Molecular and Cellular Biology and Integrative Genomics Core, City of Hope, Duarte, California, USA.
5
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
6
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA.
7
Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
8
Department of Urology, Stanford University School of Medicine, Stanford, California, USA.
9
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.

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.

PMID:
28288111
PMCID:
PMC5559385
DOI:
10.1038/nm.4309
[Indexed for MEDLINE]
Free PMC Article

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