This research will study the cis-elements and trans-acting factors that control expression of the Drosophila dopa decarboxylase gene (Ddc)in specific neuronal subsets in the CNS. Of particular interest is an identified cis-element and putative trans-factor regulating expression in a subset of serotonin neurons. The role of this factor, the homeodomain gene xfh2, in Ddc expression and in the development of serotonin and dopamine neurons will be determined via a combined genetic and biochemical approach. Additional factors that bind to this region will be isolated. Additional genes expressed in serotonin and dopamine neurons will be isolated and studied, both for a comparative analysis of their regulatory regions, and to isolate regulatory cassettes that can be used to express metabolically and developmentally important genes products in specific cellular patterns. It appears that alternative splicing is a major determinant of tissue-specific gene expression in. the CNS. The cis-elements and trans-factors important for alternative splicing of Ddc will be studied biochemically using a cell culture system and in vivo. Many strains generated in these studies will have altered levels of serotonin and dopamine in defined CNS neurons. These will be assayed for altered circadian and learning behaviors, potentially yielding insights as to the roles of particular transmitters in regions of the CNS. These studies are being performed in a model system that allows experimental manipulation not possible in vertebrate systems. Many of the enzymes and regulatory factors of this system are conserved between flies and vertebrates, indicating that the information gained is likely to be generally relevant to analogous vertebrate systems.
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