THYROID HORMONE RECEPTORS IN DEVELOPMENT

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The long range research goal of this investigator is to elucidate the mechanism(s) of action of the thyroid hormones (TH) during development. The aim of the research proposed herein is to investigate the TH receptor in the amphibian Rana catesbeiana during developmental phases of the life cycle. This is a unique animal model for these studies. Growth, development and metamorphosis are dependent on TH and can be induced by exogenous TH, and TH receptor number (sites/nucleus) in some tissues can be increased by TH. Evidence is accumulating that the TH receptor is encoded by a c-erbA gene, and c-erbA cDNAs which encode TH binding proteins have been isolated form mammalian and avian tissues. Some of these hybridize with tadpole tissue mRNAs. These cDNAs will be used to assess the number and size of c-erbA-related mRNA species present in tadpole and frog tissues, and to determine whether there are developmentally-regulated changes in the levels of one or more of these species during the life cycle. A positive correlation of such changes with the known changes in TH receptor number during development will support the hypothesis that a c- erbA gene encodes the TH receptor. To determine if tadpole c-erbA genes encode a TH receptor, cDNA libraries constructed from tadpole tissues will be screened with the cDNA probes, the cDNA inserts of positive clones sequenced, and the properties of their protein products determined. Clones containing cDNAs which encode TH binding proteins will be tested for their ability to confer or enhance T3 responsiveness in cells low in endogenous TH receptor. Finally, studies will be performed to determine if the TH- induced increase in receptor number in developing tadpoles is due to an effect on the transcription of the relevant gene. Insufficient TH during human development results in permanent brain damage, the most severe manifestation of which is cretinism. Yet the mechanisms and regulation of TH action during this period have received relatively little attention, due in part to the difficulties of conduction such studies in fetal mammals. The proposed studies will utilize an eminently suitable animal model to investigate these important biological processes.