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

• 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

SummaryG 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.

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