The formation of skeletal muscle during development requires commitment of multipotential mesodermal stem cells to the myogenic lineage and the subsequent activation of a set of genetically unlinked muscle-specific genes encoding proteins required for the specialized functions of the skeletal muscle fiber. Whereas much has been learned about the regulatory factors that control- transcription of muscle genes associated with terminal differentiation, relatively little is known of the transcription factors that act early in the myogenic pathway to establish mesoderm and mediate commitment of stem cells to the myogenic lineage. Our laboratory has recently identified a novel homeodomain protein, Mhox, that is expressed in most, if not all mesodermally-derived cell lines, and in myogenic progenitor cells during embryogenesis, and is restricted to skeletal, cardiac and smooth muscle of adult mice. Mhox is a sequence- specific DNA binding protein that binds with high affinity to a conserved A+T-rich element in the muscle creatine kinase (MCK) enhancer that is required for MCK transcription in skeletal and cardiac myocytes. By analogy with other homeodomain proteins, which have been implicated in cell fate specification and transcriptional regulation, it is likely that Mhox plays an important role in these events in mesodermally-derived cell types. The goals of this project are to define the functions of Mhox during development, to identify and characterize the functional domains of the Mhox protein, to identify proteins with which Mhox interacts, and to characterize the cis- and trans-regulatory system that regulates Mhox gene transcription in mesodermally-derived cell types. The long range goal of this project will be to disrupt the Mhox gene through homologous recombination and determine the consequences on establishment of specific mesodermally-derived cell types. These studies will provide insight into the mechanisms involved in lineage-specific regulation of gene expression and should advance our knowledge of the mechanisms through which homeodomain proteins regulate patterns of gene expression in vertebrates.
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