Utrophin (dystrophin related protein) shares extensive sequence homology and organizational motifs with dystrophin, and is considered to be the autosomal homolog of dystrophin. Indeed, transgenic over expression of utrophin can functionally substitute for the missing dystrophin molecule and reverse the dystrophic patho-physiology in the muscles of mdx (dystrophic) mice. The utrophin gene, while ubiquitously expressed, has a highly regulated sub-cellular distribution during development, regeneration as well as in mature skeletal muscle. In mature myofibers (elongated multi-nucleated cells), utrophin is enriched at the synapse or neuromuscular junction (NMJ). The spatial distribution of utrophin in myofibers parallels the distribution of nicotinic acetylcholine receptors (nACHR) to a remarkable degree, in particular, the manner in which they are influenced by the release of growth and differentiation factors (e.g. heregulin) from motor nerves. Selective enrichment of nACHR and utrophin at the NMJ occurs, in part, due to their messages being preferentially transcribed at sub-synaptic nuclei rather than nuclei scattered along the length of the myofiber. We and others, recently demonstrated that the neurite-associated growth factor heregulin utilizes the ERK (MAP kinase) signaling pathway to promote the binding of the GABPa/b transcription factor complex to the N-Box motif of the utrophin promoter, thus activating the promoter and increasing utrophin gene expression in cultured muscle cells. ? ? Current hypotheses on the regulation of utrophin expression in muscle center on N-box dependent compartmentalized transcription of utrophin at sub-synaptic nuclei. We hypothesize that additional trans-acting factors exist and regulate the utrophin promoter. We also hypothesize that co-operability among these trans-acting factors and signaling pathways plays a role in utrophin promoter regulation. In our preliminary studies, we have identified additional trans-acting factors, their signaling pathways and describe their co-operability in utrophin promoter regulation; we have also studied heregulin mediated utrophin promoter activation in mouse muscle, in vivo. In this proposal we plan to extend these studies to better understand the molecular mechanisms of utrophin promoter regulation in skeletal muscle. ? ?
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