The formation of cardiac and skeletal muscle during embryogenesis involves commitment of mesodermal precursor cells to these two striated muscle lineages and the subsequent activation of overlapping arrays of muscle- specific genes. That cardiac and skeletal muscle cells express many of the same muscle-specific genes suggests that these muscle cell types may share common regulatory factors. However, to date, there have been no transcription factors shown to account for the overlapping patterns of muscle gene expression in these two striated muscle cell types. MEF2 is a muscle-specific DNA binding activity that recognizes a conserved A/T-rich sequence in the control regions of the majority of skeletal and cardiac muscle genes. The recent cloning of MEF2 has shown it to be encoded by four genes (mef2A-D), whose products bind DNA and activate transcription as homo- and heterodimers. During mouse embryogenesis, the mef2 genes are first expressed in precursor cells for the cardiac and skeletal muscle lineages, making them likely candidates for regulators of the striated muscle developmental programs. The goal of this proposal is to define the role of the MEF2 family of transcription factors in the control of cell determination and differentiation within the cardiac and skeletal muscle lineages. The project will have three major aims, 1) to define the functional domains of MEF2 proteins that mediate muscle-specific gene activation, to identify MEF2 accessory proteins, and to determine whether MEF2 proteins are able to regulate muscle cell proliferation and differentiation, 2) to inactivate mef2 genes by homologous recombination in transgenic mice and determine the consequences on cardiac and skeletal muscle development, and 3) to define the cis- and trans-regulatory system that controls expression of the mef2C gene in the cardiac and skeletal muscle lineages during mouse embryogenesis. These studies will contribute to an understanding of the mechanisms that regulate cardiac and skeletal muscle development as well as mechanisms that control cell type-specific gene expression in general.
