Essential Regulation of CNS Angiogenesis by the Orphan G Protein–Coupled Receptor GPR124
2010
The orphan G protein-coupled receptor GPR124/TEM5 is highly expressed in central nervous system (CNS) endothelium. Here, complete null or endothelial-specific GPR124 deletion produced embryonic lethality from CNS-specific angiogenesis arrest in forebrain and neural tube. Conversely, GPR124 overexpression throughout all adult vascular beds produced CNS-specific hyperproliferative vascular malformations. In vivo, GPR124 functioned cell-autonomously in endothelium to regulate sprouting, migration, and developmental expression of the blood-brain barrier marker Glut1, while in vitro, GPR124 mediated Cdc42-dependent directional migration to forebrain-derived, VEGF-independent cues. Our results demonstrate CNS-specific angiogenesis regulation by an endothelial receptor, and illuminate functions of the poorly understood adhesion GPCR subfamily. Further, the striking functional tropism of GPR124 marks this receptor as a therapeutic target for CNS-related vascular pathologies.
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