GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling.

Ekaterina Posokhova, Animesh Shukla, Steven Seaman, Suresh Volate, Mary Beth Hilton, Bofan Wu, Holly Morris, Deborah A Swing, Ming Zhou, Enrique Zudaire, Jeffrey S Rubin, Brad St Croix

Cell reports 2015 Jan 13

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G protein-coupled receptor 124 (GPR124) is an orphan receptor in the adhesion family of GPCRs, and previous global or endothelial-specific disruption of Gpr124 in mice led to defective CNS angiogenesis and blood-brain barriergenesis. Similar developmental defects were observed following dual deletion of Wnt7a/Wnt7b or deletion of β-catenin in endothelial cells, suggesting a possible relationship between GPR124 and canonical WNT signaling. Here, we show using in vitro reporter assays, mutation analysis, and genetic interaction studies in vivo that GPR124 functions as a WNT7A/WNT7B-specific costimulator of β-catenin signaling in brain endothelium. WNT7-stimulated β-catenin signaling was dependent upon GPR124's intracellular PDZ binding motif and a set of leucine-rich repeats in its extracellular domain. This study reveals a vital role for GPR124 in potentiation of WNT7-induced canonical β-catenin signaling with important implications for understanding and manipulating CNS-specific angiogenesis and blood-brain barrier-genesis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Ekaterina Posokhova, Animesh Shukla, Steven Seaman, Suresh Volate, Mary Beth Hilton, Bofan Wu, Holly Morris, Deborah A Swing, Ming Zhou, Enrique Zudaire, Jeffrey S Rubin, Brad St Croix. GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling. Cell reports. 2015 Jan 13;10(2):123-30