PHYSICAL CHEMISTRY OF NUCLEIC ACIDS

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The overall goals are to understand the molecular basis at the DNA sequence level for the developmental regulation of gene expression. In particular, we wish to understand the structure and the expression of the genes coding for the proteins that make up muscle fibers. Genes for a number of such proteins - actin, myosin heavy chains, myosin light chains, tropomyosin, and others - are all switched on to a high level of expression when myogenic cells undergo the myoblast to myotube differentiation step. It is proposed to characterize these muscle protein genes of the fruit fly, Drosophila. In Drosophila, these genes constitute a defined limited system for which it will be possible to obtain a relatively complete description; furthermore, in Drosophila it is possible to correlate genetic data on mutants defective in muscle function with the physical structures of the genes. It is proposed to study the DNA function with the physical structures of the genes. It is proposed to study the DNA sequences in regions around the genes which are necessary for the developmental switches in excpression by reintroducing cloned vertebrate muscle protein genes back into the chromosomes of mammalian myogenic cells in culture, and studying the switches in expression of these cloned genes when the cells are induced to undergo the myoblast to myotube differentiation step. It is further proposed to clone and characterize the genes that code for the acetyl choline receptors which occur at nerve-muscle synapses. This system is an excellent example of a multi-subunit membrane bound complex at the cell surface which responds to an external molecular signal. The appropriate system for these studies are the receptor genes that are abundantly expressed in the electric organ of the ray, Torpedo californica. These studies will provide a deeper understanding of developmental diseases in general and of myasthenia gravis and of muscular dystrophy.