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Essential Regulation of CNS Angiogenesis by the Orphan G Protein–Coupled Receptor GPR124
Open accessAbstract
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.
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“Wnt signaling pathway including Wnt ligands, Norrins, Frizzled receptors, Lrp5/6 coreceptors, Gpr124 and Reck cofactors, and 𝛃 -catenin are critical for both vascular development and barriergenesis (138, 332, 558, 636, 682, 689);”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [332]
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Metadata
- Authors
- Kuhnert, F., Mancuso, M. R., Shamloo, A., Wang, H.-T., Choksi, V., Florek, M., Su, H., Fruttiger, M., Young, W. L., Heilshorn, S. C., & Kuo, C. J.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- University of California, San Francisco (US)
- University College London (GB)
- Corresponding author
- Kuo, Calvin J.
- ORCID
- Venue
- Science
- Published
- 2010-11-12
- Volume
- 330
- Issue
- 6006
- Pages
- 985-989
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3099479
- OpenAlex
- W2115716038
- Cited by
- 301
- References
- 32
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 17 · 2023: 16 · 2022: 29 · 2021: 23 · 2020: 17 · 2019: 21 · 2018: 18 · 2017: 20 · 2016: 20 · 2015: 19 · 2014: 22 · 2013: 16 · 2012: 20
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (5r21ns058600-02, 1dp2od006477-01)
- National Heart, Lung, and Blood Institute (R01HL074267)
- National Cancer Institute (R01CA095654, T32CA009302)
- National Institute of General Medical Sciences (T32GM007365, GM 07365)
- National Institute of Neurological Disorders and Stroke (1R21 NS058600, P01NS044155, R01NS027713, R01NS052830, P01 NS 44155, R01NS064517, R01-NS 27713, R21 NS058600, R21NS070153)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- GPR124, orphan G protein-coupled receptor, adhesion GPCRs, endothelial cells, embryonic lethality, neural tube, forebrain, vascular malformations, Cdc42, endothelial cell migration, sprouting angiogenesis, blood-brain barrier, GLUT1
- MeSH terms
- Animals, Blood Vessels, Blood-Brain Barrier, Cell Movement, Endothelium, Vascular, Mesencephalon, Mice, Transgenic, Rhombencephalon, Telencephalon, Prosencephalon, Gene Deletion, Mice, Knockout, Neovascularization, Physiologic, Endothelial Cells, Receptors, G-Protein-Coupled, Embryonic Development, Glucose Transporter Type 1, Mice, Neural Tube
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