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PMID: 21071672 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124.

Science (New York, N.Y.) ·Vol. 330 ·No. 6006 ·2010-11-12 ·Pages 985-9

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

Abstract

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.

MeSH Terms
Animals Blood Vessels/abnormalities Blood-Brain Barrier/metabolism Cell Movement Embryonic Development Endothelial Cells/physiology Endothelium, Vascular/embryology,metabolism Gene Deletion Glucose Transporter Type 1/metabolism Mesencephalon/blood supply,embryology,metabolism Mice Mice, Knockout Mice, Transgenic Neovascularization, Physiologic Neural Tube/blood supply,embryology,metabolism Prosencephalon/blood supply,embryology,metabolism Receptors, G-Protein-Coupled/genetics,metabolism Rhombencephalon/blood supply,embryology,metabolism Telencephalon/blood supply,embryology,metabolism
Chemicals
GPR124 protein, mouse Glucose Transporter Type 1 Receptors, G-Protein-Coupled Slc2a1 protein, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kuhnert Frank
Department of Medicine, Hematology Division, Stanford University, Stanford, CA 94305, USA.
Mancuso Michael R
Shamloo Amir
Wang Hsiao-Ting
Choksi Vir
Florek Mareike
Su Hua
Fruttiger Marcus
Young William L
Heilshorn Sarah C
Kuo Calvin J
References (30)
30 references, click to expand
  1. Chemokine signaling guides regional patterning of the first embryonic artery.
    Genes Dev. 2009 Oct 1;23(19):2272-7 PMID: 19797767
  2. Cell surface tumor endothelial markers are conserved in mice and humans.
    Cancer Res. 2001 Sep 15;61(18):6649-55 PMID: 11559528
  3. Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system.
    Dev Dyn. 2004 Nov;231(3):503-9 PMID: 15376331
  4. The blood-brain barrier: an overview: structure, regulation, and clinical implications.
    Neurobiol Dis. 2004 Jun;16(1):1-13 PMID: 15207256
  5. Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis.
    Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):641-6 PMID: 19129494
  6. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.
    Circ Res. 2007 Feb 2;100(2):174-90 PMID: 17272819
  7. The role of CXCL12 in the organ-specific process of artery formation.
    Blood. 2005 Apr 15;105(8):3155-61 PMID: 15626744
  8. The conditional inactivation of the beta-catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility.
    J Cell Biol. 2003 Sep 15;162(6):1111-22 PMID: 12975353
  9. Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin alpha(v)beta3 to glycosaminoglycans.
    J Biol Chem. 2006 Nov 10;281(45):34179-88 PMID: 16982628
  10. The neural tube patterns vessels developmentally using the VEGF signaling pathway.
    Development. 2004 Apr;131(7):1503-13 PMID: 14998923
  11. Genes expressed in human tumor endothelium.
    Science. 2000 Aug 18;289(5482):1197-202 PMID: 10947988
  12. Developmental angiogenesis of the central nervous system.
    Lymphat Res Biol. 2008;6(3-4):173-80 PMID: 19093790
  13. Selective ablation of alphav integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death.
    Development. 2005 Jan;132(1):165-76 PMID: 15576410
  14. There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini.
    Biochem Biophys Res Commun. 2003 Feb 14;301(3):725-34 PMID: 12565841
  15. Initial development of capillaries in the neuroepithelium of the mouse.
    J Anat. 1989 Jun;164:85-92 PMID: 2606797
  16. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins.
    Cell. 1998 Nov 13;95(4):507-19 PMID: 9827803
  17. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.
    Nature. 1996 Apr 4;380(6573):439-42 PMID: 8602242
  18. Endothelial cell polarization and chemotaxis in a microfluidic device.
    Lab Chip. 2008 Aug;8(8):1292-9 PMID: 18651071
  19. Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain.
    Nat Neurosci. 2008 Apr;11(4):429-39 PMID: 18344991
  20. Intraventricular hemorrhage in premature infants: mechanism of disease.
    Pediatr Res. 2010 Jan;67(1):1-8 PMID: 19816235
  21. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor.
    Thromb Haemost. 2004 Mar;91(3):595-605 PMID: 14983237
  22. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature.
    Science. 2008 Nov 21;322(5905):1247-50 PMID: 19023080
  23. Angiogenesis in life, disease and medicine.
    Nature. 2005 Dec 15;438(7070):932-6 PMID: 16355210
  24. Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice.
    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3058-63 PMID: 9096345
  25. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells.
    Science. 2004 May 28;304(5675):1338-40 PMID: 15060285
  26. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.
    Nature. 1996 Apr 4;380(6573):435-9 PMID: 8602241
  27. Molecular biology of the blood-brain barrier.
    Methods Mol Med. 2003;89:385-99 PMID: 12958435
  28. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts.
    Nature. 1999 Oct 14;401(6754):670-7 PMID: 10537105
  29. beta8 integrins are required for vascular morphogenesis in mouse embryos.
    Development. 2002 Jun;129(12):2891-903 PMID: 12050137
  30. Efficient, inducible Cre-recombinase activation in vascular endothelium.
    Genesis. 2008 Feb;46(2):74-80 PMID: 18257043
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1196554
Published
2010-11-12
Pages
985-9
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3099479
Subset
IM
Grants
NINDS NIH HHS · R21 NS058600 · United States
NINDS NIH HHS · R01NS27713 · United States
NINDS NIH HHS · 1R21 NS058600 · United States
NINDS NIH HHS · R01 NS052830-01 · United States
NCI NIH HHS · R01 CA095654-01 · United States
NHLBI NIH HHS · 1R01HL074267 · United States
NINDS NIH HHS · R21 NS070153 · United States
Medical Research Council · G0501711 · United Kingdom
NIH HHS · DP2 OD006477 · United States
NINDS NIH HHS · R01 NS052830 · United States
NINDS NIH HHS · 1R01NS064517 · United States
NIH HHS · 1DP2 OD006477 · United States
NHLBI NIH HHS · R01 HL074267-02 · United States
NCI NIH HHS · T32 CA009302 · United States
NINDS NIH HHS · 1R01NS052830 · United States
NINDS NIH HHS · R01 NS027713 · United States
NHLBI NIH HHS · R01 HL074267 · United States
NINDS NIH HHS · P01NS44155 · United States
NIGMS NIH HHS · GM07365 · United States
NCI NIH HHS · R01 CA095654 · United States
NINDS NIH HHS · R01 NS064517 · United States
NINDS NIH HHS · R01 NS064517-02 · United States
External Links
PubMed source DOI: 10.1126/science.1196554 PMC Full Text View journal details
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