Department
Biomedical Sciences
Document Type
Article
Publication Title
Nature Medicine
ISSN
1078-8956
Volume
23
Issue
4
DOI
10.1038/nm.4309
First Page
450
Last Page
460
Publication Date
4-1-2017
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.
Recommended Citation
Chang, J.,
Mancuso, M. R.,
Maier, C.,
Liang, X.,
Yuki, K.,
Yang, L.,
Kwong, J. W.,
Wang, J.,
Rao, V.,
Vallon, M.,
Kosinski, C.,
Zhang, J. J.,
Mah, A. T.,
Xu, L.,
Li, L.,
Gholamin, S.,
Reyes, T. F.,
Li, R.,
Kuhnert, F.,
Han, X.,
Yuan, J.,
Chiou, S.,
Brettman, A. D.,
Daly, L.,
Corney, D. C.,
Cheshier, S. H.,
Shortliffe, L. D.,
Wu, X.,
&
Snyder, M.
(2017).
Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.
Nature Medicine, 23(4), 450–460.
DOI: 10.1038/nm.4309
https://scholarlycommons.pacific.edu/dugoni-facarticles/721
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