Cardiac morphogenesis requires commitment of multipotential stem cells to the cardiac lineage and the subsequent activation of a set of genetically unlinked muscle-specific genes encoding proteins required for specialized functions of the cardiac myocyte. Whereas much has been learned about the regulatory factors that control the formation of skeletal muscle, relatively little is known of the transcription factors responsible for commitment of stem cells to the cardiac muscle lineage and transcriptional induction of cardiac muscle-specific genes. Our laboratory has recently identified a novel homeodomain protein, MHox, that is expressed in cardiac myocytes in vivo and in vitro MHox is a sequence-specific DNA binding protein which is expressed in several mesodermally-derived cell types during embryogenesis and is restricted to skeletal, cardiac and smooth muscle of adult mice. MHox binds with high affinity to a conserved A+T rich element in the muscle creating kinase (MCK) enhancer, that is required for MCK transcription in 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 within the cardiac muscle lineage. The goal of this project is the define the roles of MHox in regulation of cardiac muscle transcription and ultimately to analyze the mechanisms that regulate MHox expression during cardiac morphogenesis. We will attempt to identify target genes that they may be regulated by MHox and will define by site direct its expression in the developing heart. The long range goal of this project will be to disrupt the MHox gene through homologous recombination and determine the consequences on cardiac morphogenesis. These studies will contribute to an understanding of the mechanisms responsible for establishment and maintenance of the cardiac muscle phenotype and should advance our knowledge of the mechanisms through this homeodomain proteins regulates patterns of gene expression in vertebrate systems.
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