This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paul, B. D. Articles by Shi, Y.-B. Search for Related Content PubMed PubMed Citation Articles by Paul, B. D. Articles by Shi, Y.-B.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2005, p. 5712-5724, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5712-5724.2005

Coactivator Recruitment Is Essential for Liganded Thyroid Hormone Receptor To Initiate Amphibian Metamorphosis

Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 18T, Rm. 106, Bethesda, Maryland 20892

Received 14 September 2004/ Returned for modification 19 October 2004/ Accepted 25 March 2005

Thyroid hormone receptors (TRs) can repress or activate target genes depending on the absence or presence of thyroid hormone (T3), respectively. This hormone-dependent gene regulation is mediated by recruitment of corepressors in the absence of T3 and coactivators in its presence. Many TR-interacting coactivators have been characterized in vitro. In comparison, few studies have addressed the developmental roles of these cofactors in vivo. We have investigated the role of coactivators in transcriptional activation by TR during postembryonic tissue remodeling by using amphibian metamorphosis as a model system. We have previously shown that steroid receptor coactivator 3 (SRC3) is expressed and upregulated during metamorphosis, suggesting a role in gene regulation by liganded TR. Here, we have generated transgenic tadpoles expressing a dominant negative form of SRC3 (F-dnSRC3). The transgenic tadpoles exhibited normal growth and development throughout embryogenesis and premetamorphic stages. However, transgenic expression of F-dnSRC3 inhibits essentially all aspects of T3-induced metamorphosis, as well as natural metamorphosis, leading to delayed or arrested metamorphosis or the formation of tailed frogs. Molecular analysis revealed that F-dnSRC3 functioned by blocking the recruitment of endogenous coactivators to T3 target genes without affecting corepressor release, thereby preventing the T3-dependent gene regulation program responsible for tissue transformations during metamorphosis. Our studies thus demonstrate that coactivator recruitment, aside from corepressor release, is required for T3 function in development and further provide the first example where a specific coactivator-dependent gene regulation pathway by a nuclear receptor has been shown to underlie specific developmental events.

This article has been cited by other articles:

• Matsuda, H., Paul, B. D., Choi, C. Y., Shi, Y.-B. (2007). Contrasting Effects of Two Alternative Splicing Forms of Coactivator-Associated Arginine Methyltransferase 1 on Thyroid Hormone Receptor-Mediated Transcription in Xenopus laevis. Mol. Endocrinol. 21: 1082-1094 [Abstract] [Full Text]  
• Paul, B. D., Buchholz, D. R., Fu, L., Shi, Y.-B. (2007). SRC-p300 Coactivator Complex Is Required for Thyroid Hormone-induced Amphibian Metamorphosis. J. Biol. Chem. 282: 7472-7481 [Abstract] [Full Text]  
• Buchholz, D. R., Paul, B. D., Shi, Y.-B. (2005). Gene-specific Changes in Promoter Occupancy by Thyroid Hormone Receptor during Frog Metamorphosis: IMPLICATIONS FOR DEVELOPMENTAL GENE REGULATION. J. Biol. Chem. 280: 41222-41228 [Abstract] [Full Text]