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This version published online on January 15, 2004
Endocrinology, doi:10.1210/en.2003-1209
A more recent version of this article appeared on May 1, 2004
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Submitted on September 11, 2003
Accepted on January 8, 2004

Both TR{beta}1 and TR{beta}2 isoforms contribute to the regulation of hypothalamic TRH

Sandrine M. Dupré, Hajer Guissouma, Frédéric Flamant, Isabelle Seugnet, Thomas S. Scanlan, John D. Baxter, Jacques Samarut, Barbara A. Demeneix*, and Nathalie Becker

Muséum National d'Histoire Naturelle, USM 501 département Régulation, Développement et Diversité Moléculaire, CNRS UMR 5166, 75231 Paris Cedex 05, France. Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, UMR CNRS 5665 LA INRA 913, 46 Allée d'Italie, 69364 Lyon Cedex 07, France. Metabolic Research Unit, Department of Pharmaceutical Chemistry and Molecular and Cellular Pharmacology, University of California, San Fransisco, CA 94143, USA.

* To whom correspondence should be addressed. E-mail: becker{at}mnhn.fr.

Thyroid hormones (TH) are essential regulators of vertebrate development and metabolism. Central mechanisms governing their production have evolved, with the {beta} thyroid hormone receptor (TR{beta}) playing a key regulatory role in the negative feedback effects of circulating TH levels on production of hypothalamic TRH and hypophyseal TSH. Both thyroid hormone receptor {beta} isoforms (TR{beta}1 and TR{beta}2) are expressed in the hypothalamus and pituitary. However, their respective roles in TH-dependent transcriptional regulation of TRH are undefined. We confirmed the preferential role of TR{beta} vs. TR{alpha} isoforms in TRH regulation in wild-type mice in vivo by using the TR{beta} preferential agonist, GC-1. We next determined the effects of tissue-specific rescue of TR{beta}1 and TR{beta}2 isoforms by somatic gene transfer in hypothalami of TR{beta} null (TR{beta}-) mice. TH-dependent TRH transcriptional repression was impaired in TR{beta}- mice, but repression was restored by co-transfection of either TR{beta}1 or TR{beta}2 into the hypothalamus. TR{beta}1, but not TR{beta}2, displayed a role in ligand-independent activation. In situ hybridization was used to examine endogenous TRH expression in the paraventricular nucleus of the hypothalamus of TR{beta}- or TR{alpha} null (TR{alpha}o/o) mice under different thyroid states. In contrast to published data on TR{beta}2- mice, we found that both ligand-independent TRH activation and ligand-dependent TRH repression were severely impaired in TR{beta}- mice. This study thus provides functional in vivo data showing that both TR{beta}1 and {beta}2 isoforms have specific roles in regulating TRH transcription.
Key words: Thyrotropin-releasing hormone • transcriptional regulation • thyroid hormone receptors • knock-out mice




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