An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates.

Michelle America, Naguissa Bostaille, Marie Eubelen, Maud Martin, Didier Y R Stainier, Benoit Vanhollebeke

Cell reports 2022 May 31

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Within the central nervous system, Wnt7a/b are unambiguously discriminated from other Wnt ligands by an endothelial receptor complex made of the glycosylphosphatidylinositol (GPI)-anchored Reck and the adhesion G protein-coupled receptor (GPCR) Gpr124. Reck is a Wnt7a/b-specific receptor, while Gpr124 facilitates the delivery of Reck-bound Wnt7a/b ligands to Frizzled, through partially characterized mechanisms. We report that, in zebrafish, the Gpr124-Frizzled interactions are dominated by intracellular scaffolds that exploit the striking molecular mimicry between Gpr124 and Frizzled intracellular domains (ICDs): an internal Dvl-binding motif and a C-terminal ETTV motif that recruits Dlg4 and Magi3. By contrast, mammalian Gpr124 receptors exhibit an ICD-independent interaction mechanism governed by species-specific attributes of their transmembrane and extracellular domains. This mechanism seemingly evolved to replace the Dvl-mediated mechanism. By contrasting zebrafish, mouse, and human Gpr124, this study provides insights into the evolution of Gpr124/Reck function across the vertebrate clade, a receptor complex uniquely implicated in Wnt ligand-specific cellular responses. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Michelle America, Naguissa Bostaille, Marie Eubelen, Maud Martin, Didier Y R Stainier, Benoit Vanhollebeke. An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates. Cell reports. 2022 May 31;39(9):110902