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GPR124, a brain endothelial adhesion seven-pass transmembrane protein, associates with RECK, which binds and stabilizes newly synthesized WNT7 that is transferred to frizzled (FZD) to initiate canonical \u03b2-catenin signaling. GPR124 remains enigmatic: although its extracellular domain (ECD) is essential, the poorly conserved intracellular domain (ICD) appears to be variably required in mammals versus zebrafish, potentially via adaptor protein bridging of GPR124 and FZD ICDs. GPR124 ICD deletion impairs zebrafish angiogenesis, but paradoxically retains WNT7 signaling upon mammalian transfection. We thus investigated GPR124 ICD function using the mouse deletion mutant Gpr124\u0394C. Despite inefficiently expressed GPR124\u0394C protein, Gpr124\u0394C\/\u0394C mice could be born with normal cerebral cortex angiogenesis, in comparison with Gpr124\u2212\/\u2212 embryonic lethality, forebrain avascularity and hemorrhage. Gpr124\u0394C\/\u0394C vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124\u0394C protein expression. Furthermore, Gpr124\u0394C and the recombinant GPR124 ECD rescued WNT7 signaling in culture upon brain endothelial Gpr124 knockdown. Thus, in mice, GPR124-regulated CNS forebrain angiogenesis and BBB function are exerted by ICD-independent functionality, extending the signaling mechanisms used by adhesion seven-pass transmembrane receptors.<\/jats:p>","DOI":"10.1242\/dev.202794","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T08:21:50Z","timestamp":1714378910000},"source":"Crossref","is-referenced-by-count":16,"title":["GPR124 regulates murine brain embryonic angiogenesis and BBB formation by an intracellular domain-independent mechanism"],"prefix":"10.1242","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2719-1906","authenticated-orcid":false,"given":"Kanako","family":"Yuki","sequence":"first","affiliation":[{"name":"Stanford University School of Medicine 1 Department of Medicine, Division of Hematology , , Stanford, CA 94305 , 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