Mechanisms of TGF-b regulation of muscle differentiation

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DESCRIPTION: (provided by applicant): The overall goal in this proposal is to establish physiologically relevant models about how TGF-Beta signaling through the Smad pathway regulates the terminal differentiation of skeletal muscle cells. The first part of the project aims to characterize the mechanism(s) through which TGF-Beta-activated Smads repress the function of MyoD family of myogenic bHLH transcription factors and inhibit muscle differentiation. Specifically, these experiments will extend our initial finding about a role for Smad3 in repression of muscle-specific transcription by determining the underlying mechanism(s), as well as the contribution of each potential mechanism to the antagonistic effect of TGF-beta during myogenesis. The second aim of this proposal is to evaluate the physical and functional interaction between Smads and MEF2 family of transcription factors, and elucidate the impact of such interaction on myogenic differentiation. Finally, since it is important to extend the role of Smad signaling in myogenesis in vivo, we will determine the consequence of altered Smad3 function to the differentiation of myoblast cells injected to normal skeletal muscle tissues and myofiber regeneration following injury and in muscle dystrophy mouse models. Our study on the myogenic regulatory function of Smads will provide new insights on how TGF-beta and peptide growth factors in general, regulate mesenchymal cell differentiation.