Muscle development proceeds through an evolutionarily conserved series of events, including myoblast generation and migration, myotube formation and attachment to tendons, sarcomerogenesis and myofiber maturation. In the course of this process, stem-cell-like muscle precursors differentiate forming syncytial tubes with a specialized contractile apparatus. Drosophila adult muscles, which exhibit developmental plasticity and functional diversification similar to that observed in vertebrates, include fibrilla and tubular types. Tubular muscles are similar to vertebrate striated muscle, while fibrilar indirect flight muscles (IFMs) share some features with cardiomyocytes. Defects in muscle development, and possibly in the specification of muscle types, can result in disorders, for example muscular dystrophies or congenital heart defects, which result in debilitating and life-threatening conditions. Recently, Spalt major (Salm) was characterized as a master regulator both necessary and sufficient to mediate the switch to the fibrillar muscle identity in Drosophila. However, the detailed mechanisms of fibrillar muscle construction remain unclear. Here I propose to combine RNA-Seq with ChIP-Seq to characterize the Salm mediated transcriptional switch and identify Salm effectors that execute fibrillogenesis. I will perform a developmental RNA-Seq timecourse to characterize dynamic expression changes during flight-muscle development and perform ChIP-Seq to identify direct Salm targets. As alternative splicing plays a major role in myogenesis and alternatively spliced gene isoforms are misexpressed in Salm RNAi flies, I hypothesized that Salm regulates differential splicing. I propose to investigate the splicing factor Arrest to gain mechanistic insight into how Salm induced alternative splicing may dictate the development of fibrillar tissue. Dissection of the Salm mediated transcriptional switch and its molecular effectors will elucidate mechanisms of sarcomerogenesis that should be relevant to vertebrate myogenesis.
The basic functional unit of muscle, the sarcomere, is conserved from jellyfish to humans. Changes in both the structural and catalytic components of muscle are observed between developmental stages, muscle-types, physiological adaptations and pathological conditions. Understanding foundational mechanisms of myogenesis and muscle-type specific sarcomerogenesis will likely provide insights into pathological conditions, such as muscular dystrophies, cardiac defects and age-related muscle weakness, where the normal development, aging and structural composition of muscle is disrupted.
|Spletter, Maria L; Schnorrer, Frank (2014) Transcriptional regulation and alternative splicing cooperate in muscle fiber-type specification in flies and mammals. Exp Cell Res 321:90-8|