Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.
Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.
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DOI：
10.1038/nm.4309
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发表时间：
2017-04
期刊：
影响因子：
82.9
通讯作者：
Kuo CJ
中科院分区：
文献类型：
--
作者：
Chang J;Mancuso MR;Maier C;Liang X;Yuki K;Yang L;Kwong JW;Wang J;Rao V;Vallon M;Kosinski C;Zhang JJ;Mah AT;Xu L;Li L;Gholamin S;Reyes TF;Li R;Kuhnert F;Han X;Yuan J;Chiou SH;Brettman AD;Daly L;Corney DC;Cheshier SH;Shortliffe LD;Wu X;Snyder M;Chan P;Giffard RG;Chang HY;Andreasson K;Kuo CJ
尽管血脑屏障(BBB)受损是多种中枢神经系统(CNS)疾病的主要病因，但控制BBB功能的内皮受体蛋白的定义尚不明确。据报道，内皮G蛋白偶联受体GPR124是小鼠胚胎正常前脑血管生成和血脑屏障功能所必需的，但该受体在成年动物中的作用尚不清楚。在这里，成年小鼠血管内皮细胞中的GPR124条件性基因敲除并不影响体内平衡的血脑屏障的完整性，但在缺血性中风和胶质母细胞瘤的小鼠模型中，却导致血脑屏障的破坏和微血管出血，并伴随着脑血管规范的Wnt-β-Catenin信号的减少。Wnt-β-catenin信号的结构性激活完全纠正了GPR124-Cko小鼠的血脑屏障破坏和出血缺陷，挽救了内皮基因紧密连接、周细胞覆盖和细胞外基质缺陷。因此，我们确定GPR124是成年小鼠病理条件下内皮细胞Wnt信号转导和血脑屏障完整性所特需的内皮GPCRs。这一发现表明GPR124可能成为治疗以血脑屏障中断为特征的人类中枢神经系统疾病的潜在靶点。
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.
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DOI：
10.1073/pnas.1019761108
发表时间：
2011-02-15
影响因子：
11.1
作者：
Anderson, Keith D.;Pan, Li;Gale, Nicholas W.
通讯作者：
Gale, Nicholas W.
影响因子：
64.5
作者：
Junge, Harald J.;Yang, Stacey;Ye, Weilan
通讯作者：
Ye, Weilan
Wnt/β-catenin信号传导控制血脑屏障的发展。
影响因子：
7.8
作者：
Liebner, Stefan;Corada, Monica;Bangsow, Thorsten;Babbage, Jane;Taddei, Andrea;Czupalla, Cathrin J.;Reis, Marco;Felici, Angelina;Wolburg, Hartwig;Fruttiger, Marcus;Taketo, Makoto M.;von Melchner, Harald;Plate, Karl Heinz;Gerhardt, Holger;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
3.7
作者：
Daneman R;Zhou L;Agalliu D;Cahoy JD;Kaushal A;Barres BA
通讯作者：
Barres BA
DOI：
10.1083/jcb.201212032
发表时间：
2013-07-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen ZL;Yao Y;Norris EH;Kruyer A;Jno-Charles O;Akhmerov A;Strickland S
通讯作者：
Strickland S