WNT/β-catenin signaling plays a crucial role in myoblast fusion through regulation of nephrin expression during development.

Skeletal muscle development is controlled by a series of multiple orchestrated regulatory pathways. WNT/β-catenin is one of the most important pathways for myogenesis; however, it remains unclear how this signaling pathway regulates myogenesis in a temporal- and spatial-specific manner. Here, we show that WNT/β-catenin signaling is crucial for myoblast fusion through regulation of the nephrin (Nphs1) gene in the Myog-Cre-expressing myoblast population. Mice deficient for the β-catenin gene in Myog-Cre-expressing myoblasts (Ctnnb1F/F;Myog-Cre mice) displayed myoblast fusion defects, but not migration or cell proliferation defects. The promoter region of Nphs1 contains the conserved β-catenin-binding element, and Nphs1 expression was induced by the activation of WNT/β-catenin signaling. The induction of Nphs1 in cultured myoblasts from Ctnnb1F/F;Myog-Cre mice restored the myoblast fusion defect, indicating that nephrin is functionally relevant in WNT/β-catenin-dependent myoblast fusion. Taken together, our results indicate that WNT/β-catenin signaling is crucial for myoblast fusion through the regulation of the Nphs1 gene.