Myomerger induces fusion of non-fusogenic cells and is required for myoblast fusion

Despite the importance of cell fusion for mammalian development and physiology, the factors critical for this process remain to be fully defined 1 . This lack of knowledge has severely limited our ability to reconstitute cell fusion, which is necessary to decipher the biochemical mechanisms driving plasma membrane merger. Myomaker ( Tmem8c ) is a muscle-specific protein required for myoblast fusion 2,3 . Expression of myomaker in fibroblasts drives their fusion with myoblasts, but not with other myomaker-fibroblasts, highlighting the requirement of additional myoblast-derived factors for fusion. Here, we demonstrate that Gm7325 , named myomerger, induces the fusion of myomaker-expressing fibroblasts. Cell mixing experiments reveal that while myomaker renders cells fusion-competent, myomerger induces fusogenicity. Thus, myomaker and myomerger confer fusogenic activity to normally non-fusogenic cells. Myomerger is skeletal muscle-specific and only expressed during developmental and regenerative myogenesis. Disruption of myomerger in myoblast cell lines through Cas9-mutagenesis generated non-fusogenic myocytes. Genetic deletion of myomerger in mice results in a paucity of muscle fibers demonstrating a requirement for myomerger in normal muscle formation. Myomerger deficient myocytes exhibit an ability to differentiate and harbor organized sarcomeres, however remain mono-nucleated. These data identify myomerger as a fundamental myoblast fusion protein and establishes a system that begins to reconstitute mammalian cell fusion.