Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt Signaling
Open accessAbstract
Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a coactivator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp coreceptor and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific coactivator of canonical Wnt signaling.
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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.
“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 [689]
The Introduction (page not supplied) says canonical Wnt signaling is central to CNS vascular development and barrier formation, and identifies Wnt7a/b, Norrin, Frizzled4, and Lrp5/6. The Discussion (page not supplied) identifies Gpr124 as a co-activator. Our copy does not identify Reck as a cofactor, so it does not support the full list attributed to this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBoth cerebral angiogenesis and BBB formation require precise cues from various growth factors, guidance molecules and other factors such as microRNA, as well as fine tuning of intracellular signaling pathways and gene expression.
“Both cerebral angiogenesis and BBB formation require precise cues from various growth factors, guidance molecules and other factors such as microRNA, as well as fine tuning of intracellular signaling pathways and gene expression (22, 628, 682, 689).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [689]
The Introduction (page unavailable) says Wnt7a and Wnt7b promote CNS angiogenesis and BBB formation through endothelial Wnt signaling, and the Discussion describes the importance of signaling strength for vascular development and barrier maintenance. These passages support the claim about molecular cues and fine-tuned signaling, but our copy does not establish the asserted roles of guidance molecules or microRNA. (LLM, conf=0.87)
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References 28 · Cited by 265
Research works printed but not linked: 26
- Anderson KD Pan L Yang XM Hughes VC Walls JR Dominguez MG Simmons MV Burfeind P Xue YZ Wei Y 2011 Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor Proc Natl Acad Sci USA 108 2807 2812 21282641 PMC3041062
- Carson-Walter EB Watkins DN Nanda A Vogelstein B Kinzler KW Croix BS 2001 Cell surface tumor endothelial markers are conserved in mice and humans Cancer Res 61 6649 6655 11559528
- Claxton S Kostourou V Jadeja S Chambon P Hodivala-Dilke K Fruttiger M 2008 Efficient, inducible Cre-recombinase activation in vascular endothelium Genesis 46 74 80 18257043
- Cullen M Elzarrad MK Seaman S Zudaire E Stevens J Yang MY Li XJ Chaudhary A Xu LH Hilton MB 2011 GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier Proc Natl Acad Sci USA 108 5759 5764 21421844 PMC3078373
- Daneman R Agalliu D Zhou L Kuhnert F Kuo CJ Barres BA 2009 Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis vol 106, pg 641, 2009 Proc Natl Acad Sci USA 106 6422 6422 PMC2626756 19129494
- Goodwin AM Sullivan KM D'Amore PA 2006 Cultured endothelial cells display endogenous activation of the canonical Wnt signaling pathway and express multiple ligands, receptors, and secreted modulators of Wnt signaling Dev Dynam 235 3110 3120 17013885
- Harada N Tamai Y Ishikawa T Sauer B Takaku K Oshima M Taketo MM 1999 Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene Embo J 18 5931 5942 10545105 PMC1171659
- Hebert JM McConnell SK 2000 Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures Dev Biol 222 296 306 10837119
- Hu J Dong AW Fernandez-Ruiz V Shan JJ Kawa M Martinez-Anso E Prieto J Qian C 2009 Blockade of Wnt Signaling Inhibits Angiogenesis and Tumor Growth in Hepatocellular Carcinoma Cancer Res 69 6951 6959 19690140
- Janda CY Waghray D Levin AM Thomas C Garcia KC 2012 Structural Basis of Wnt Recognition by Frizzled Science 337 59 64 22653731 PMC3577348
- Joiner DM Ke JY Zhong ZD Xu HE Williams BO 2013 LRP5 and LRP6 in development and disease Trends Endocrin Met 24 31 39 PMC3592934 23245947
- Junge HJ Yang S Burton JB Paes K Shu X French DM Costa M Rice DS Ye WL 2009 TSPAN12 Regulates Retinal Vascular Development by Promoting Norrin- but Not Wnt-Induced FZD4/beta-Catenin Signaling Cell 139 299 311 19837033
- Liebner S Corada M Bangsow T Babbage J Taddei A Czupalla CJ Reis M Felici A Wolburg H Fruttiger M 2008 Wnt/beta-catenin signaling controls development of the blood-brain barrier J Cell Biol 183 409 417 18955553 PMC2575783
- MacDonald BT Semenov MV Huang H He X 2011 Dissecting Molecular Differences between Wnt Coreceptors LRP5 and LRP6 Plos One 6 e23537 21887268 PMC3160902
- Maretto S Cordenonsi M Dupont S Braghetta P Broccoli V Hassan AB Volpin D Bressan GM Piccolo S 2003 Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors Proc Natl Acad Sci USA 100 3299 3304 12626757 PMC152286
- Nikopoulos K Venselaar H Collin RWJ Riveiro-Alvarez R Boonstra FN Hooymans JMM Mukhopadhyay A Shears D van Bers M de Wijs IJ 2010 Overview of the Mutation Spectrum in Familial Exudative Vitreoretinopathy and Norrie Disease with Identification of 21 Novel Variants in FZD4, LRP5, and NDP Hum Mutat 31 656 666 20340138
- Paes KT Wang E Henze K Vogel P Read R Suwanichkul A Kirkpatrick LL Potter D Newhouse MM Rice DS 2011 Frizzled 4 Is Required for Retinal Angiogenesis and Maintenance of the Blood-Retina Barrier Invest Ophth Vis Sci 52 6452 6461 21743011
- St Croix B Rago C Velculescu V Traverso G Romans KE Montgomery E Lal A Riggins GJ Lengauer C Vogelstein B 2000 Genes expressed in human tumor endothelium Science 289 1197 1202 10947988
- Stenman JM Rajagopal J Carroll TJ Ishibashi M McMahon J McMahon AP 2008 Canonical Wnt Signaling Regulates Organ-Specific Assembly and Differentiation of CNS Vasculature Science 322 1247 1250 19023080
- Wang YS Huso D Cahill H Ryugo D Nathans J 2001 Progressive cerebellar, auditory, and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene J Neurosci 21 4761 4771 11425903 PMC6762346
- Wang YS Rattner A Zhou YL Williams J Smallwood PM Nathans J 2012 Norrin/Frizzled4 Signaling in Retinal Vascular Development and Blood Brain Barrier Plasticity Cell 151 1332 1344 23217714 PMC3535266
- Xu Q Wang YS Dabdoub A Smallwood PM Williams J Woods C Kelley MW Jiang L Tasman W Zhang K 2004 Vascular development in the retina and inner ear: Control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair Cell 116 883 895 15035989
- Ye X Smallwood P Nathans J 2011 Expression of the Norrie disease gene (Ndp) in developing and adult mouse eye, ear, and brain Gene Expr Patterns 11 151 155 21055480 PMC3061303
- Ye X Wang YS Cahill H Yu MZ Badea TC Smallwood PM Peachey NS Nathans J 2009 Norrin, Frizzled-4, and Lrp5 Signaling in Endothelial Cells Controls a Genetic Program for Retinal Vascularization Cell 139 285 298 19837032 PMC2779707
- Ye X Wang YS Nathans J 2010 The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease Trends Mol Med 16 417 425 20688566 PMC2963063
- Zhou Y Wang Y Tischfield M Williams J Smallwood PM Rattner A Taketo MM Jeremy Nathans J 2014 Canonical WNT signaling components in vascular development and barrier formation J Clinical Invest Epub ahead of print PMC4151216 25083995
- Authors
- Zhou, Y., & Nathans, J.
- Affiliations
- Johns Hopkins University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Nathans, Jeremy
- ORCID
- Nathans, Jeremy
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 31
- Issue
- 2
- Pages
- 248-256
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC4223636
- OpenAlex
- W2000293457
- Cited by
- 265
- References
- 28
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 20 · 2023: 23 · 2022: 30 · 2021: 23 · 2020: 24 · 2019: 27 · 2018: 25 · 2017: 28 · 2016: 14 · 2015: 17 · 2014: 1
- FWCI
- 10.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Eye Institute (EY018637, R01EY018637)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- GPR124, adhesion G protein-coupled receptors, Wnt/β-catenin signaling, blood-brain barrier, endothelial cells, Wnt7a, Wnt7b, Frizzled receptors, transcriptional coactivator
- MeSH terms
- Animals, Blood-Brain Barrier, Cell Line, Central Nervous System, Eye Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Proto-Oncogene Proteins, Mice, Knockout, Neovascularization, Physiologic, Endothelial Cells, Receptors, G-Protein-Coupled, Wnt Proteins, Frizzled Receptors, Mice, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-5
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