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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.

Pubmed ID: 21071672

Authors

  • Kuhnert F
  • Mancuso MR
  • Shamloo A
  • Wang HT
  • Choksi V
  • Florek M
  • Su H
  • Fruttiger M
  • Young WL
  • Heilshorn SC
  • Kuo CJ

Journal

Science (New York, N.Y.)

Publication Data

November 12, 2010

Associated Grants

  • Agency: NIH HHS, Id: 1DP2 OD006477
  • Agency: NHLBI NIH HHS, Id: 1R01HL074267
  • Agency: NINDS NIH HHS, Id: 1R01NS052830
  • Agency: NINDS NIH HHS, Id: 1R01NS064517
  • Agency: NINDS NIH HHS, Id: 1R21 NS058600
  • Agency: Medical Research Council, Id: G0501711
  • Agency: NIGMS NIH HHS, Id: GM07365
  • Agency: NINDS NIH HHS, Id: P01NS44155
  • Agency: NCI NIH HHS, Id: R01 CA095654
  • Agency: NCI NIH HHS, Id: R01 CA095654-01
  • Agency: NHLBI NIH HHS, Id: R01 HL074267
  • Agency: NHLBI NIH HHS, Id: R01 HL074267-02
  • Agency: NINDS NIH HHS, Id: R01 NS052830
  • Agency: NINDS NIH HHS, Id: R01 NS052830-01
  • Agency: NINDS NIH HHS, Id: R01 NS064517
  • Agency: NINDS NIH HHS, Id: R01 NS064517-02
  • Agency: NINDS NIH HHS, Id: R01NS27713
  • Agency: NINDS NIH HHS, Id: R21 NS070153
  • Agency: NCI NIH HHS, Id: T32 CA009302

Mesh Terms

  • Animals
  • Blood Vessels
  • Blood-Brain Barrier
  • Cell Movement
  • Embryonic Development
  • Endothelial Cells
  • Endothelium, Vascular
  • Gene Deletion
  • Glucose Transporter Type 1
  • Mesencephalon
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neovascularization, Physiologic
  • Neural Tube
  • Prosencephalon
  • Receptors, G-Protein-Coupled
  • Rhombencephalon
  • Telencephalon