Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124.
The orphan G protein-coupled receptor (GPCR) GPR124/tumor endothelial marker 5 is highly expressed in central nervous system (CNS) endothelium. Here, we show that complete null or endothelial-specific GPR124 deletion resulted in 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, whereas in vitro, GPR124 mediated Cdc42-dependent directional migration to forebrain-derived, vascular endothelial growth factor-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 functional tropism of GPR124 marks this receptor as a therapeutic target for CNS-related vascular pathologies.
Department of Medicine, Hematology Division, Stanford University, Stanford, CA 94305, USA.
Frank
F
Kuhnert
Michael R
MR
Mancuso
Amir
A
Shamloo
Hsiao-Ting
HT
Wang
Vir
V
Choksi
Mareike
M
Florek
Hua
H
Su
Marcus
M
Fruttiger
William L
WL
Young
Sarah C
SC
Heilshorn
Calvin J
CJ
Kuo
D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities; D001812:Blood-Brain Barrier / Q000378:metabolism; D002465:Cell Movement; D047108:Embryonic Development; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000196:embryology / Q000378:metabolism; D017353:Gene Deletion; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D008636:Mesencephalon / Q000098:blood supply / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D054259:Neural Tube / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism; D016548:Prosencephalon / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012249:Rhombencephalon / Q000098:blood supply / Q000196:embryology / Q000378:metabolism; D013687:Telencephalon / Q000098:blood supply / Q000196:embryology / Q000378:metabolism
C554106:GPR124 protein, mouse; D051272:Glucose Transporter Type 1; D043562:Receptors, G-Protein-Coupled; C495678:Slc2a1 protein, mouse