Precise targeting of myotubes to muscle attachment sites patterns the musculoskeletal system

Summary Nascent myotubes undergo a dramatic morphological transformation during myogenesis in which the myotubes elongate over several cell diameters and choose the correct muscle attachment sites. Although this process of myotube guidance is essential to pattern the musculoskeletal system, the mechanisms that control myotube guidance remain poorly understood. Using transcriptomics, we found that components of the Fibroblast Growth Factor (FGF) signaling pathway were enriched in nascent myotubes in Drosophila embryos. Null mutations in the FGF receptor heartless ( htl ), or its ligands, caused significant myotube guidance defects. Mechanistically, paracrine FGF signals to Htl in the mesoderm regulate the activity of Rho/Rac GTPases in nascent myotubes to effect changes in the actin cytoskeleton. FGF signals are thus essential regulators of myotube guidance that act through cytoskeletal regulatory proteins to pattern the musculoskeletal system.