THYROID HORMONE CONTROL OF A GENE EXPRESSION NETWORK

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Amphibian metamorphosis presents an excellent opportunity to study how hormones control gene expression networks in a tissue-specific and development stage-specific manner. During the transition from the larval tadpole to the adult frog, thyroid hormone controls the growth and differentiation of new adult structures, the remodeling of existing structures for a an adult frog, thyroid hormone lysis of entire larval organs. These morphogenetic changes are caused by gene expression changes mediated by the nuclear thyroid hormone receptors. Subtractive hybridization and candidate gene approaches have identified between twenty and thirty thyroid hormone induced and repressed genes in the reabsorbing tadpole tail, an example of hormonally controlled programmed cell death examined the downstream am signaling events that culminate in tissue specific biological responses. Furthermore, current methods such native chrromatin. We propose to determine the mechanism of thyroid hormone activation of genes that are among the last to be induced in this gene expression cascade. The genes we have chosen to study encode a secreted matrix metalloproteinase, collagenase-3 , and an intra cellular cell death inducing protease, caspase-3. Collagenase- 3 is the most strongly up-regulated gene in dying muscle cells. We will use two complementary approaches to identify and characterize the Th- responsive and basal regulatory elements in these two sequenced. The ideal test of a candidate regulatory sequence is whether or not it can support appropriate transcriptional regulation in vivo. Thus, we will recently developed transenic technologies in Xenopus laevis to screen for the minimal genomic fragment genomic DNA from the collagenase-3 and caspase-3 genes will be screened for sequences that bind to early induced transcription bind to important regulatory sequences will be functionally characterized in vivo using transgenic tadpoles, employing both gain- and hormone-induced gene expression cascade from the time of thyroid hor more binding to its receptors to the induction of a concepts, and molecular markers identified during the proposed work can be applied to other important yet complex biological problems. These include thyroid hormone control of the growth and differentiation of the amphibian limbs, and certainly steroid and thyroid hormone control of gene networks in adult and developing mammals.