A conserved molecular pathway mediates myoblast fusion in insects and vertebrates.

Skeletal muscles arise by fusion of precursor cells, myoblasts, into multinucleated fibers. In vertebrates, mechanisms controlling this essential step in myogenesis remain poorly understood. Here we provide evidence that Kirrel, a homolog of receptor proteins that organize myoblast fusion in Drosophila melanogaster, is necessary for muscle precursor fusion in zebrafish. Within developing somites, Kirrel expression localized to membranes of fusion-competent myoblasts of the fast-twitch lineage. Unlike wild-type myoblasts that form spatially arrayed syncytial (multinucleated) fast myofibers, those deficient in Kirrel showed a significant reduction in fusion capacity. Inhibition of Rac, a GTPase and the most downstream intracellular transducer of the fusion signal in D. melanogaster, also compromised fast-muscle precursor fusion in zebrafish. However, unlike in D. melanogaster, constitutive Rac activation in zebrafish led to hyperfused giant syncytia, highlighting an entirely new function for this protein in zebrafish for gating the number and polarity of fusion events. These findings uncover a substantial degree of evolutionary conservation in the genetic regulation of myoblast fusion.