Role of MEF2C in muscle development and regeneration

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Muscular dystrophies are debilitating diseases that affect about one out of every 3500 live male births. Several therapeutic strategies for muscular dystrophy are aimed at the capacity of satellite cells or other muscle associated stem cells to repair damaged muscle fibers. Importantly, recent evidence has shown that the regulatory pathways functioning during muscle regeneration share many common features with the myogenic program that functions during skeletal muscle development. Thus, the long term objective of the studies proposed here is to define fully the transcriptional pathways governing skeletal muscle development, regeneration, and repair. One family of transcription factors that plays a key role in skeletal muscle development is the myocyte enhancer factor 2 (MEF2) family. MEF2 proteins function as part of a combinatorial transcriptional complex with members of the MyoD family of basic helix-loop-helix (bHLH) proteins, which are essential for muscle specification and differentiation during development and also play critical roles in satellite cell proliferation and differentiation. The studies proposed here will define the transcriptional regulation and genetic function of the mef2c gene in skeletal muscle. Because MEF2 transcription factors play an essential role in muscle differentiation, it is important to define the regulation and function of these genes during muscle development. A better understanding of these developmental pathways is essential for the development of therapies based on increasing regenerative capacity in skeletal muscle. This study will address the following two specific aims: 1. To determine the function of mef2c in skeletal muscle. Using conditional targeting approaches in mice, the mef2c gene has been specifically ablated in skeletal muscle. The development, function, and regenerative capacity of skeletal muscle without mef2c will be analyzed using histology, molecular markers and analyses of muscle function. Downstream targets will be identified by microarray analyses. 2. To define the regulators of mef2c transcription in skeletal muscle. Recently, a small enhancer and promoter fragment from the mef2c gene that is sufficient to direct expression exclusively to skeletal muscle in transgenic mice was identified. The studies proposed here will define c/s-acting elements that are required for expression in transgenic mice and will identify the trans-acting factors that regulate mef2c.