Genetic regulation of muscle fiber diversity. The long-term goal of this project is to create a developmental regulatory framework to describe how diverse skeletal muscle fiber types are specified. Mammalian muscles contain distinct fiber types with unique physiologies; however the manner in which fiber-type development occurs has yet to be fully elucidated. We use the Drosophila system to understand mechanisms of muscle fiber differentiation, by analyzing the development of two distinct muscles in the adult thorax: the flight muscles and jump muscles, which are members of two distinct fiber types. In the current period of support, we discovered that the transcription factors Extradenticle (Exd) and Homothorax (Hth) activate a regulatory cascade involving another transcription factor, Spalt-major (Salm), and the CELF-related splicing factor Arrest (Aret). This network promotes specification of the flight muscles through direct activation of at least one flight muscle structual gene, and through direct regulation of flight muscle- specific alternative splicing events. Each factor can also promote flight muscle fate in the jump muscle, indicating that they are critical to fiber-specific gene regulation. Importantly, Exd, Hth and Aret have vertebrate homologs known to function in promoting fast fiber fate. In the next period of support, we will build upon this framework to generate a complete view of how fiber-specific identity is controlled, and expand our analysis to define how jump muscle differentiation is controlled. We will also investigate how the transcriptional pathways for formation of individual fiber types interact with one another to maintain their own identity, and to suppress formation of the other fiber type. Given that Exd, Hth and Aret each have vertebrate orthologs that contribute to fiber-specific gene regulation, our studies stand to provide critical new insight into mechanisms of muscle formation in vertebrates, and will generate a framework for understanding the basis of fiber-specific gene regulation in mammalian development and disease.
Understanding the transcriptional programs that control muscle fiber specification is a major area of investigation in muscle biology. Moreover, a number of human muscle diseases preferentially affect one class of muscles over another. By defining mechanisms for how individual muscle arises in the body, our studies will provide a deeper understanding of how some muscles might be more sensitive to the development of pathologies, and how the symptoms of such diseases might be ameliorated. The Drosophila system has a noted history of being used to define basic cellular and molecular processes that function in development and disease in higher animals.
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