Congenital myopathies (CM) are a heterogeneous collection of disorders defined by early onset hypotonia. Some myopathies can progress to extreme conditions in which patients develop respiratory complications and even require assistance for mobility. Mutations in genes associated with actin dynamics have been identified in patients with CMs, including Tropomyosins. We found that Drosophila Tropomyosin 2 (Tm2) directs embryonic skeletal muscle development by promoting myoblast fusion, myotube elongation, and sarcomere assembly. These surprising results argue that defects in myofiber development contribute to the clinical phenotypes associated with CMs. There remain critical knowledge gaps in our understanding of skeletal muscle development. In particular, nascent myotubes must elongate and attach to the appropriate tendon cells to form a functional contractile unit. However, the molecules that guide myotubes to their muscle attachment sites remain largely unknown. In addition, the mechanisms by which myotubes respond to chemotactic signals are unclear. We have used forward genetic screens and cutting edge transcriptional profiling to identify myotube guidance molecules and intracellular effectors of myotube elongation. Our preliminary work has generated unique genetic tools and novel mechanistic insights that will allow us to characterize the central pathways and mechanisms that direct myotube elongation. The overall hypothesis for this application is that filopodia are the key effectors of myotube pathfinding, and that filopodial behavior is dictated by external pathfinding cues, intracellular protein kinases, and actin regulatory proteins. This project will achieve the following aims: (1) define the cellular pathways by which Tropomyosin regulates myogenesis, (2) characterize novel intracellular effectors of myotube pathfinding, and (3) characterize chemotactic mechanisms that direct myotube pathfinding. These studies will make substantial inroads into an emerging area of muscle biology that has the potential to uncover novel mechanisms that contribute to muscle disease.
This project will provide novel insights into the molecular pathways that orchestrate muscle morphogenesis. Congenital myopathies are due in part to defects in muscle development. The pathways identified in this study will directly enhance our understanding of congenital myopathy disease mechanisms.
