| First Author | Yuki K | Year | 2024 |
| Journal | Development | Volume | 151 |
| Issue | 11 | PubMed ID | 38682276 |
| Mgi Jnum | J:350577 | Mgi Id | MGI:7662811 |
| Doi | 10.1242/dev.202794 | Citation | Yuki K, et al. (2024) GPR124 regulates murine brain embryonic angiogenesis and BBB formation by an intracellular domain-independent mechanism. Development 151(11) |
| abstractText | The GPR124/RECK/WNT7 pathway is an essential regulator of CNS angiogenesis and blood-brain barrier (BBB) function. 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 beta-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 Gpr124DeltaC. Despite inefficiently expressed GPR124DeltaC protein, Gpr124DeltaC/DeltaC mice could be born with normal cerebral cortex angiogenesis, in comparison with Gpr124-/- embryonic lethality, forebrain avascularity and hemorrhage. Gpr124DeltaC/DeltaC vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124DeltaC protein expression. Furthermore, Gpr124DeltaC 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. |
