This project will explore the molecular mechanisms responsible for the specific pattern of contractile isoform gene expression in craniofacial development. Our previous experiments showed that there is a distinct pattern of myogenic regulatory factor (e.g. MyoD gene family) gene expression in the tongue - quite different from the well described patterns observed in limb and trunk muscles. The overall hypothesis to be tested in this proposal is that this distinctive pattern of regulatory factor expression is responsible for the physiological phenotype of tongue muscle through its control over the pattern of contractile isoform gene expression. This hypothesis will be tested by molecular genetic analysis of mechanisms that regulate specific genes in myogenic cells in vitro, and in vivo, in the tongues of mice following attempts to modify the pattern of myogenic regulatory factor gene expression. The long term goals of this project are to determine the molecular mechanisms regulating the tissue and fiber type specific patterns of gene expression in developing and adult craniofacial muscles. Our objectives are to test the hypothesis that the differential expression of the various contractile isoforms is critical for the function of individual muscles of the head and neck. The pattern of isoform expression in craniofacial muscles is developmentally regulated, as it is in limb and trunk muscles, but the pattern of myogenic regulatory factor (MRF) gene expression that we have discovered in tongue development appears to be distinct. We propose that this craniofacial pattern of myogenic regulatory factors (i.e the MyoD gene family members) is responsible in turn for the specific patterns of expression of their targets, the contractile protein gene isoforms. based on these observations we will attempt to elucidate the molecular mechanisms controlling the tissue specific and developmentally regulated expression of the troponin C genes during craniofacial development. Specifically we will: 1) test the hypothesis that there are protein-protein interactions between myogenic regulatory factors and accessory factors that interact with the distal enhancer and the proximal promoter of the fast-twitch troponin C gene (TnCf); 2) test the hypothesis that the pattern of myogenic regulatory factor and Troponin C gene expression in developing tongue muscle is modulated by extrinsic factors; and 3) test the hypothesis that alteration in myogenic regulatory factor (MRF) ratio or expression will alter the contractile isoform expression pattern (i.e. fast versus slow contractile isoforms) and thereby determine the phenotype of the myofiber.
Showing the most recent 10 out of 39 publications
