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

Authors

• Junlei Chang, Stanford University School of Medicine
• Michael R. Mancuso, Stanford University School of Medicine
• Carolina Maier, Stanford University School of Medicine
• Xibin Liang, Stanford University School of Medicine
• Kanako Yuki, Stanford University School of Medicine
• Lu Yang, City of Hope National Med Center
• Jeffrey W. Kwong, Stanford University School of Medicine
• Jing Wang, Stanford University School of Medicine
• Varsha Rao, Stanford University School of Medicine
• Mario Vallon, Stanford University School of Medicine
• Cynthia Kosinski, Stanford University School of Medicine
• J. J. Haijing Zhang, Stanford University School of Medicine
• Amanda T. Mah, Stanford University School of Medicine
• Lijun Xu, Stanford University School of Medicine
• Le Li, Stanford University School of Medicine
• Sharareh Gholamin, Stanford University School of Medicine
• Teresa F. Reyes, Stanford University School of Medicine
• Rui Li, Stanford University School of Medicine
• Frank Kuhnert, Stanford University School of Medicine
• Xiaoyuan Han, Stanford University School of MedicineFollow
• Jenny Yuan, Stanford University School of Medicine
• Shin Heng Chiou, Stanford University School of Medicine
• Ari D. Brettman, Stanford University School of Medicine
• Lauren Daly, Stanford University School of Medicine
• David C. Corney, Stanford University School of Medicine
• Samuel H. Cheshier, Stanford University School of Medicine
• Linda D. Shortliffe, Stanford University School of Medicine
• Xiwei Wu, City of Hope National Med Center
• Michael Snyder, Stanford University School of Medicine

Department

Biomedical Sciences

Document Type

Article

Publication Title

Nature Medicine

ISSN

1078-8956

Volume

23

Issue

4

DOI

10.1038/nm.4309

First Page

450

Last Page

460

Publication Date

4-1-2017

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.

Recommended Citation

Chang, J., Mancuso, M. R., Maier, C., Liang, X., Yuki, K., Yang, L., Kwong, J. W., Wang, J., Rao, V., Vallon, M., Kosinski, C., Zhang, J. J., Mah, A. T., Xu, L., Li, L., Gholamin, S., Reyes, T. F., Li, R., Kuhnert, F., Han, X., Yuan, J., Chiou, S., Brettman, A. D., Daly, L., Corney, D. C., Cheshier, S. H., Shortliffe, L. D., Wu, X., & Snyder, M. (2017). Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nature Medicine, 23(4), 450–460. DOI: 10.1038/nm.4309
https://scholarlycommons.pacific.edu/dugoni-facarticles/721

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