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Molecular and Cellular Biology, December 2002, p. 8527-8538, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8527-8538.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Nuclear Receptor Corepressor Recruitment by Unliganded Thyroid Hormone Receptor in Gene Repression during Xenopus laevis Development

Laurent M. Sachs,1,2* Peter L. Jones,1,{dagger} Emmanuelle Havis,2 Nicole Rouse,1 Barbara A. Demeneix,2 and Yun-Bo Shi1*

Unit on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-5431,1 Laboratoire de Physiologie Générale et Comparée, UMR-8572 CNRS, Muséum National d'Histoire Naturelle, 75231 Paris cedex 05, France2

Received 16 May 2002/ Returned for modification 25 June 2002/ Accepted 24 September 2002

Thyroid hormone receptors (TR) act as activators of transcription in the presence of the thyroid hormone (T3) and as repressors in its absence. While many in vitro approaches have been used to study the molecular mechanisms of TR action, their physiological relevance has not been addressed. Here we investigate how TR regulates gene expression during vertebrate postembryonic development by using T3-dependent amphibian metamorphosis as a model. Earlier studies suggest that TR acts as a repressor during premetamorphosis when T3 is absent. We hypothesize that corepressor complexes containing the nuclear receptor corepressor (N-CoR) are key factors in this TR-dependent gene repression, which is important for premetamorphic tadpole growth. To test this hypothesis, we isolated Xenopus laevis N-CoR (xN-CoR) and showed that it was present in pre- and metamorphic tadpoles. Using a chromatin immunoprecipitation assay, we demonstrated that xN-CoR was recruited to the promoters of T3 response genes during premetamorphosis and released upon T3 treatment, accompanied by a local increase in histone acetylation. Furthermore, overexpression of a dominant-negative N-CoR in tadpole tail muscle led to increased transcription from a T3-dependent promoter. Our data indicate that N-CoR is recruited by unliganded TR to repress target gene expression during premetamorphic animal growth, an important process that prepares the tadpole for metamorphosis.

* Corresponding author. Mailing address for Yun-Bo Shi: Laboratory of Gene Regulation and Development, NICHD, NIH, Building 18T, Room 106, Bethesda, MD 20892. Phone: (301) 402-1004. Fax: (301) 402-1323. E-mail: shi{at}helix.nih.gov. Mailing address for Laurent M. Sachs: Laboratoire de Physiologie, UMR-8572 CNRS, MNHN, 7 rue Cuvier, 75231 Paris cedex 05, France. Phone: 33 1 40 79 36 04. Fax: 33 1 40 79 36 18. E-mail: sachs{at}mnhn.fr.

{dagger} Present address: Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.

Molecular and Cellular Biology, December 2002, p. 8527-8538, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8527-8538.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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