Post-mitotic myotubes repurpose the cytokinesis machinery to effect cellular guidance

Myotube guidance is an essential step of muscle development that ultimately establishes the final musculoskeletal pattern, yet the mechanisms that guide post-mitotic myotubes to the correct skeletal attachment sites are poorly understood. Here, we describe a novel myogenic pathway that is regulated by the previously uncharacterized Vaccinia Related Kinase (VRK) family member Back Seat Driver (Bsd). Bsd modulates microtubule dynamics to direct myotube guidance in Drosophila embryos, and preserves cellular identity by preventing myotube-myotube fusion. Mechanistically, Bsd activates Polo kinase in nascent myotubes to regulate cellular guidance. Tumbleweed (Tum) is an essential Polo effector during cytokinesis, and we show Tum performs a critical role in attachment site selection. We also found that the mammalian Bsd orthologue Vrk3 is required for myotube morphogenesis, and that Vrk3 activates the Polo orthologue Plk1. Our studies have uncovered a conserved pathway in which Bsd activates the cytokinesis machinery in post-mitotic cells to direct myotube guidance.