Coactivator recruitment is essential for liganded thyroid hormone receptor to initiate amphibian metamorphosis

Bindu Paul, Liezhen Fu, Daniel R. Buchholz, Yun Bo Shi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5712-5724
Number of pages13
JournalMolecular and Cellular Biology
Volume25
Issue number13
DOIs
StatePublished - Jul 2005
Externally publishedYes

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Thyroid Hormone Receptors
Amphibians
Co-Repressor Proteins
Nuclear Receptor Coactivator 3
Genes
Larva
Triiodothyronine
Cytoplasmic and Nuclear Receptors
Growth and Development
Anura
Transcriptional Activation
Embryonic Development
Hormones

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Coactivator recruitment is essential for liganded thyroid hormone receptor to initiate amphibian metamorphosis. / Paul, Bindu; Fu, Liezhen; Buchholz, Daniel R.; Shi, Yun Bo.

In: Molecular and Cellular Biology, Vol. 25, No. 13, 07.2005, p. 5712-5724.

Research output: Contribution to journalArticle

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