GPR124 Functions as a WNT7-Specific Coactivator of Canonical β-Catenin Signaling

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 deletio...

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Published in:	Cell reports (Cambridge) 2015-01, Vol.10 (2), p.123-130
Main Authors:	Posokhova, Ekaterina, Shukla, Animesh, Seaman, Steven, Volate, Suresh, Hilton, Mary Beth, Wu, Bofan, Morris, Holly, Swing, Deborah A., Zhou, Ming, Zudaire, Enrique, Rubin, Jeffrey S., St. Croix, Brad
Format:	Article
Language:	eng
Subjects:	Amino Acid Motifs Animals beta Catenin - metabolism Blood-Brain Barrier - metabolism Brain - cytology Brain - metabolism Endothelial Cells - cytology Endothelial Cells - metabolism HEK293 Cells Humans Mice Mice, Knockout Mice, Transgenic PDZ Domains Proto-Oncogene Proteins - metabolism Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - deficiency Receptors, G-Protein-Coupled - metabolism Wnt Proteins - metabolism Wnt Signaling Pathway
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Summary:	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 barriergenesis. [Display omitted] •GPR124 is a WNT7-specific coactivator of β-catenin signaling in brain endothelium•GPR124/WNT7 genetic interaction studies support a common signaling pathway in vivo•GPR124’s four-amino-acid C terminus is required for optimal WNT7/β-catenin signaling•GPR124’s N-terminal leucine-rich repeats are required for WNT7/β-catenin signaling Members of the Wnt family signal through multiple frizzled receptors, but mechanisms that govern Wnt signaling specificity remain unclear. Here, Posokhova et al. show that GPR124 functions as a WNT7A/WNT7B-specific coactivator of β-catenin signaling in brain endothelium with important implications for understanding and manipulating CNS-specific angiogenesis and barriergenesis.
ISSN:	2211-1247 2211-1247