This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dupré, S. M. Articles by Becker, N. Search for Related Content PubMed PubMed Citation Articles by Dupré, S. M. Articles by Becker, N.

Both Thyroid Hormone Receptor (TR)ß1 and TRß2 Isoforms Contribute to the Regulation of Hypothalamic Thyrotropin-Releasing Hormone

Muséum National d’Histoire Naturelle (S.M.D., H.G., I.S., B.A.D., N.B.), Unité Scientifique du Muséum 501 Département Régulation, Développement et Diversité Moléculaire, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5166, 75231 Paris Cedex 05, France; Laboratoire de Biologie Moléculaire et Cellulaire de l’Ecole Normale Supérieure de Lyon (F.F., J.S.), CNRS, UMR 5665 Laboratoire Associé Institut National de la Recherche Agronomique 913, 69364 Lyon Cedex 07, France; and the Metabolic Research Unit, Department of Pharmaceutical Chemistry and Molecular and Cellular Pharmacology (T.S.S., J.D.B.), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Barbara A. Demeneix or Dr. Nathalie Becker, Muséum National d’Histoire Naturelle, Unité Scientifique du Muséum 501 Département Régulation, Développement et Diversité Moléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5166, 75231 Paris Cedex 05, France. E-mail: demeneix{at}mnhn.fr or becker{at}mnhn.fr.

Thyroid hormones (TH) are essential regulators of vertebrate development and metabolism. Central mechanisms governing their production have evolved, with the ß-TH receptor (TRß) playing a key regulatory role in the negative feedback effects of circulating TH levels on production of hypothalamic TRH and hypophyseal TSH. Both TRß-isoforms (TRß1 and TRß2) 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 TRß vs. TR isoforms in TRH regulation in wild-type mice in vivo by using the TRß preferential agonist GC-1. We next determined the effects of tissue-specific rescue of TRß1 and TRß2 isoforms by somatic gene transfer in hypothalami of TRß null (TRß^–/–) mice. TH-dependent TRH transcriptional repression was impaired in TRß^–/– mice, but was restored by cotransfection of either TRß1 or TRß2 into the hypothalamus. TRß1, but not TRß2, 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 TRß^–/– or TR null (TR^o/o) mice under different thyroid states. In contrast to published data on TRß2^–/– mice, we found that both ligand-independent TRH activation and ligand-dependent TRH repression were severely impaired in TRß^–/– mice. This study thus provides functional in vivo data showing that both TRß1 and TRß2 isoforms have specific roles in regulating TRH transcription.

This article has been cited by other articles:

				S. V H Grommen, L. Arckens, T. Theuwissen, V. M Darras, and B. De Groef Thyroid hormone receptor {beta}2 is strongly up-regulated at all levels of the hypothalamo-pituitary-thyroidal axis during late embryogenesis in chicken J. Endocrinol., March 1, 2008; 196(3): 519 - 528. [Abstract] [Full Text] [PDF]

				A. A. Nikrodhanond, T. M. Ortiga-Carvalho, N. Shibusawa, K. Hashimoto, X. H. Liao, S. Refetoff, M. Yamada, M. Mori, and F. E. Wondisford Dominant Role of Thyrotropin-releasing Hormone in the Hypothalamic-Pituitary-Thyroid Axis J. Biol. Chem., February 24, 2006; 281(8): 5000 - 5007. [Abstract] [Full Text] [PDF]

				W. Wan, B. Farboud, and M. L. Privalsky Pituitary Resistance to Thyroid Hormone Syndrome Is Associated with T3 Receptor Mutants that Selectively Impair {beta}2 Isoform Function Mol. Endocrinol., June 1, 2005; 19(6): 1529 - 1542. [Abstract] [Full Text] [PDF]