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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055511-02
Application #
6177426
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1999-05-15
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
2
Fiscal Year
2000
Total Cost
$142,350
Indirect Cost
Name
University of California Davis
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Furlow, J David; Neff, Eric S (2006) A developmental switch induced by thyroid hormone: Xenopus laevis metamorphosis. Trends Endocrinol Metab 17:40-7
Weidner, W Jeffrey; Waddell, David S; Furlow, J David (2006) Measurement of the filtration coefficient (Kfc) in the lung of Gallus domesticus and the effects of increased microvascular permeability. J Comp Physiol B 176:567-74
Luria, Ayala; Furlow, J David (2004) Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos. Proc Natl Acad Sci U S A 101:8987-92
Lim, Wayland; Furlow, J David (2002) Ribozyme suppression of endogenous thyroid hormone receptor activity in Xenopus laevis cells. Nucleic Acids Res 30:3490-6
Furlow, J David; Kanamori, Akira (2002) The transcription factor basic transcription element-binding protein 1 is a direct thyroid hormone response gene in the frog Xenopus laevis. Endocrinology 143:3295-305
Lim, Wayland; Nguyen, Ngoc-Ha; Yang, Ha Yung et al. (2002) A thyroid hormone antagonist that inhibits thyroid hormone action in vivo. J Biol Chem 277:35664-70