reproduced verbatim): The long term goals are to understand how steroid hormones regulate diverse patterns of development within the CNS. Studies on the insect models, Drosophila melonogaster and Manduca sexta, have shown that ecdysteroids can activate two discrete developmental programs depending on steroid concentration. Low steroid levels control tissue patterning and cellular determination while high steroid concentrations promote cell maturation. Ecdysteropid action is mediated through the ecdysone receptor (EcR) and its heterodimer partner ultraspiracle (USP). A mosaic analysis of clonal tissues that lacks USP suggests that the transcriptional silencing and transcriptional activation functions of the EcR/USP complex have different developmental functions; the former primarily mediating programs of tissue patterning and cell determination while the latter is involved in programs of cellular maturation. Insights gained about how these silencing and activational functions of the EcR/USP complex relate to developmental programs in these insect models will also be directly applicable to understanding homologous signaling systems in vertebrates -- those mediating the actions of thyroid hormone and the retinoids.
Specific aims are: 1) determine the receptors and signaling molecules that cause the pre-metamorphic changes in Drosophila. 2) Use a mosaic analysis to determine the role of the ligand binding and DNA binding domains of EcR in mediating the two programs of developmental response. 3) Use the mosaic analysis of EcR mutants and the misexpression of EcR isoforms to examine the ability of each isoform to support patterning and determination processes versus maturational processes. 4) Use USP clones and in vitro challenges with ecdysteroids to examine how cell determination and cell maturation programs interact during development. 5) Utilize a neuron-myoblast coculture system to examine how neurons are able to direct the type of EcR isoform expressed in embryonic muscle and how receptor isoform choice relates to muscle growth and maturation responses.
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