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

被引：200

作者：

Chang, Junlei ^{[1
,11
]}

Mancuso, Michael R. ^{[1
]}

Maier, Carolina ^{[2
]}

Liang, Xibin ^{[3
]}

Yuki, Kanako ^{[1
]}

Yang, Lu ^{[4
,5
]}

Kwong, Jeffrey W. ^{[1
]}

Wang, Jing ^{[3
]}

Rao, Varsha ^{[6
]}

Vallon, Mario ^{[1
]}

Kosinski, Cynthia ^{[1
]}

Zhang, J. J. Haijing ^{[1
]}

Mah, Amanda T. ^{[1
]}

Xu, Lijun ^{[7
]}

Li, Le ^{[7
]}

Gholamin, Sharareh ^{[2
]}

Reyes, Teresa F. ^{[1
]}

Li, Rui ^{[8
]}

Kuhnert, Frank ^{[1
]}

Han, Xiaoyuan ^{[9
]}

Yuan, Jenny ^{[1
]}

Chiou, Shin-Heng ^{[6
]}

Brettman, Ari D. ^{[1
]}

Daly, Lauren ^{[1
]}

Corney, David C. ^{[1
]}

Cheshier, Samuel H. ^{[2
]}

Shortliffe, Linda D. ^{[9
]}

Wu, Xiwei ^{[4
,5
]}

Snyder, Michael ^{[6
]}

Chan, Pak ^{[2
]}

Giffard, Rona G. ^{[7
]}

Chang, Howard Y. ^{[8
,10
]}

Andreasson, Katrin ^{[3
]}

Kuo, Calvin J. ^{[1
]}

机构：

[1] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, Stanford, CA 94305 USA

[4] City Hope Natl Med Ctr, Dept Mol & Cellular Biol, Duarte, CA USA

[5] City Hope Natl Med Ctr, Integrat Genom Core, Duarte, CA USA

[6] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[7] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA

[8] Stanford Univ, Dept Dermatol, Sch Med, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Urol, Sch Med, Stanford, CA 94305 USA

[10] Stanford Univ, Ctr Personal Dynam Regulomes, Sch Med, Stanford, CA 94305 USA

[11] Chinese Acad Sci, Shenzhen Inst Adv Technol, Inst Biomed & Biotechnol, Ctr Antibody Drug, Shenzhen, Peoples R China

来源：

NATURE MEDICINE | 2017年 / 23卷 / 04期

关键词：

RETINAL VASCULAR DEVELOPMENT; TUMOR-SUPPRESSOR PROTEIN; CEREBRAL-HEMORRHAGE; ENDOTHELIAL-CELLS; COUPLED RECEPTOR; CNS ANGIOGENESIS; PERICYTES; EXPRESSION; NORRIN; BETA;

D O I：

10.1038/nm.4309

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-b-catenin signaling. Constitutive activation of Wnt-b-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.

引用

页码：450 / +

页数：14

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