β-Catenin is essential for differentiation of primary myoblasts via cooperation with MyoD and α-catenin

Canonical Wnts promote myoblast differentiation; however, the role of beta-catenin in adult myogenesis has been contentious, and its mechanism(s) unclear. Using CRISPR-generated beta-catenin-null primary adult mouse myoblasts, we found that beta-catenin was essential for morphological differentiation and timely deployment of the myogenic gene program. Alignment, elongation and fusion were grossly impaired in null cells, and myogenic gene expression was not coordinated with cytoskeletal and membrane remodeling events. Rescue studies and genome-wide analyses extended previous findings that a beta-catenin-TCHLEF interaction is not required for differentiation, and that beta-catenin enhances MyoD binding to myogenic loci. We mapped cellular pathways controlled by beta-catenin and defined novel targets in myoblasts, including the fusogenic genes myomaker and myomixer. We also showed that interaction of beta-catenin with alpha-catenin was important for efficient differentiation. Overall the study suggests dual roles for beta-catenin: a TCF/LEF-independent nuclear function that coordinates an extensive network of myogenic genes in cooperation with MyoD; and an alpha-catenin-dependent membrane function that helps control cell-cell interactions. beta-Catenin-TCF/LEF complexes may function primarily in feedback regulation to control levels of beta-catenin and thus prevent precocious/excessive myoblast fusion.