Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.

Abstract

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

• Authors: Junlei Chang, Michael R Mancuso, Carolina Maier, Xibin Liang, Kanako Yuki, Lu Yang, Jeffrey W Kwong, Jing Wang, Varsha Rao, Mario Vallon, Cynthia Kosinski, J J Haijing Zhang, Amanda T Mah, Lijun Xu, Le Li, Sharareh Gholamin, Teresa F Reyes, Rui Li, Frank Kuhnert, Xiaoyuan Han, Jenny Yuan, Shin-Heng Chiou, Ari D Brettman, Lauren Daly, David C Corney, Samuel H Cheshier, Linda D Shortliffe, Xiwei Wu, Michael Snyder, Pak Chan, Rona G Giffard, Howard Y Chang, Katrin Andreasson, Calvin J Kuo
• Journal: Nature medicine (Nat Med) Vol. 23 Issue 4 Pg. 450-460 (Apr 2017) ISSN: 1546-170X [Electronic] United States
• PMID: 28288111 (Publication Type: Journal Article)

Chemical References

• GPR124 protein, mouse
• Receptors, G-Protein-Coupled

Topics

• Animals
• Blood-Brain Barrier (metabolism, ultrastructure)
• Disease Models, Animal
• Endothelial Cells (metabolism, ultrastructure)
• Extracellular Matrix (metabolism)
• Flow Cytometry
• Fluorescent Antibody Technique
• Glioblastoma (genetics, metabolism)
• Infarction, Middle Cerebral Artery (genetics, metabolism)
• Intracranial Hemorrhages (genetics, metabolism)
• Mice
• Mice, Knockout
• Microscopy, Electron
• Microvessels
• Pericytes (ultrastructure)
• Real-Time Polymerase Chain Reaction
• Receptors, G-Protein-Coupled (genetics)
• Tight Junctions (metabolism, ultrastructure)
• Wnt Signaling Pathway