The molecular and developmental functions of skeletal muscle regulatory genes will be investigated. Nuclear and cell biological experiments will focus on analysis of the specific roles of these regulatory genes in the embryonic determination and subsequent differentiation of avian and mammalian skeletal myoblasts. Genomic DNA and cDNA transfection approaches will be used to characterized the myd gene and other regulatory genes that control the activation of the helix/loop/helix (HLH) myogenic regulatory genes, MyoD1, myf5 and myogenin, in mammalian and avian skeletal muscle myoblasts. Biochemical approaches also will be used to identify regulatory factors that control the transcriptional activity of the MyoD1 promoter in myoblasts. The temporal and spatial expression of these myogenic regulatory genes in developing avian embryos will be determined by in situ hybridization. Immunohistological and clonal cell culture techniques will identify the embryonic sites where myoblast lineage determination occurs. Finally, homologous recombination/insertion mutagenesis and antisense oligonucleotide inhibition strategies will be used to create null mutations of MyoD1 and other myogenic regulatory genes in cultured primary human aNd embryonic quail myoblasts. These studies will define the specific functions of these regulatory genes in the determination of myoblast lineages, in the growth factor control of myoblast cell division and the initiation of differentiation, and in the coordinate transcriptional activation of muscle protein genes during myoblAst differentiation. An understanding of the regulatory mechanisms that control the development of skeletal muscle may provide methods to regenerate diseased muscles and insights into molecular genetic abnormalities of cell growth and differentiation in tumor cells.
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