Dual role of brain endothelial Gpr126 in blood-brain barrier development and ischemic stroke

Abstract

The blood–brain barrier (BBB) acquires unique properties for regulation of the neuronal function during development. The genesis of the BBB coupled with angiogenesis is orchestrated by the Wnt/β–catenin signaling pathway. Aside from the importance of Wnt/β–catenin signaling, the molecular mechanisms that regulate these processes are poorly understood. Here, we identify the brain endothelial adhesion G–protein–coupled receptor Gpr126 as a novel target gene of Wnt/β–catenin signaling that is required for postnatal BBB development, and its expression is detrimental for ischemic stroke in adults. We show that Gpr126 expression is high in mouse brain endothelium during BBB formation, but decreases in the adult. Inactivation of Gpr126 in postnatal endothelial cells results in vessel enlargement and impairs acquisition of the BBB characteristics, such as increased neurovascular permeability, and reduced basement membrane protein deposition and pericyte coverage. Mechanistically, Gpr126 is required during developmental angiogenesis to promote endothelial cell migration, acting via an interaction between Lrp1 and β1–integrin, which couples vessel morphogenesis to BBB formation. Interestingly, in adult mice with an established BBB, the lack of Gpr126 expression in acute ischemic stroke is protective and coupled with reduced microglia activation, which contributes to an improved neurological outcome. These data identify Gpr126 as a promising therapeutic target to treat ischemic stroke.

Structure, ligands, and roles of GPR126/ADGRG6 in the development and diseases

“…In a recent preprinted manuscript, GPR126 was found to co-immunoprecipitate with α3β1-integrin, but not with the α1β1-integrin. 27 Meanwhile, GPR126 was demonstrated to interact with Lrp1 and α3β1-integrin, facilitating the GPR126-mediated functions in cell migration. 27 In future studies, the question of whether GPR126 interaction with Lrp1 and α3β1-integrin has an important role in Schwann cell myelination needs to be further explored.…”