An important model system for understanding nuclear receptor signaling during development is metamorphosis of the frog Xenopus laevis. Thyroid hormone induces remarkable functional and morphogenetic changes as the larval tadpole transitions into the adult frog. A great deal of progress has been made on the molecular mechanisms of thyroid hormone receptor function in all vertebrates. Besides characterization of the highly conserved thyroid hormone receptor genes themselves, several receptor interacting proteins have been identified that mediate their ability to repress or activate transcription in the absence or presence of ligand, respectively. These coactivators and corepressors, collectively termed coregulators, recruit complexes that modify target gene chromatin or modulate RNA polymerase II access to hormone responsive promoters. Differential expression and/or activity of coregulator complexes have been suggested to influence cell and promoter specific responses to a given hormone, but these experiments have mostly relied on transient transfection and in vitro transcription systems or gene knockout technologies that deprive the animal of these genes from fertilization onward. Our central hypothesis is that the balance of ligand-dependent coactivation and ligand-independent corepression is critical for proper temporal and spatial responses to thyroid hormone during metamorphosis. To test this hypothesis, we will develop transgenic tadpoles that allow us to determine the precise pattern of thyroid hormone receptor mediated transcription in living tadpoles. We will then correlate coactivator and corepressor gene expression with the onset of developmental competence to respond to natural and synthetic Iigands and the tissue specificity of those responses. The relative importance of corepressor and coactivator interactions with the thyroid hormone receptor in vivo will then be tested by two strategies: first, by treatment with NH-3, a compound that disrupts both coactivator and corepressor interaction with the thyroid hormone receptor; and second, by tissue specific and inducible expression of full-length and dominant negative corepressor proteins. Finally, we will analyze gene expression networks regulated by TH in proliferating regions of the brain and jaw cartilage. We are particularly interested in determining the molecular basis for the selective agonism of NH-3 on neuronal versus cartilage proliferation. This selective agonism/antagonism is a common feature of estrogen receptor modulators such as tamoxifen but has not been previously described for thyroid hormone receptors. These last studies will provide new information on gene expression cascades leading to cellular proliferation in two tissues that are dependent on TH for proper development in both amphibians and mammals, including humans. In summary, Xenopus laevis metamorphosis is a powerful model for determining the role of thyroid hormone receptors and their coregulators in tissue specific control of gene expression networks during vertebrate development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055511-06
Application #
7006600
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
1999-05-15
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
6
Fiscal Year
2006
Total Cost
$184,924
Indirect Cost
Name
University of California Davis
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
047120084
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