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Dominant Inhibition of Thyroid Hormone Action Selectively in the Pituitary of Thyroid Hormone Receptor-ß Null Mice Abolishes the Regulation of Thyrotropin by Thyroid Hormone

Division of Endocrinology (E.D.A.), Metabolism and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112; Departamento de Ciencias Fisiologicas (E.G.M.), Instituto de Biologia, Universidade do Estado do Rio de Janeiro, 20550-030 Rio de Janeiro, Brazil; Division of Endocrinology (R.S.A.), Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Human Genetics (A.C.-B., D.F.), Mount Sinai School of Medicine, New York, New York 10029; Laboratorio de Endocrinologia Molecular (C.C.P.-M.), Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21000-000 Rio de Janeiro, Brazil; Division of Endocrinology and Metabolism (M.-E.B., H.C.K.), Beth Israel Deaconess Medical Center, Boston Massachusetts 02215; and Section of Endocrinology and Metabolism (F.E.W.), Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637

Address all correspondence to: E. Dale Abel, Division of Endocrinology, Metabolism and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, 15 North 2030 East, Building 533, Room 3410B, Salt Lake City, Utah 84112. E-mail: dale.abel{at}hmbg.utah.edu. Address reprint requests to: Fredric E. Wondisford, Section of Endocrinology and Metabolism, Pritzker School of Medicine, The University of Chicago, 5841 South Maryland Avenue MC1027, Chicago, Illinois 60637.

Thyroid hormones, T₄ and T₃, regulate their own production by feedback inhibition of TSH and TRH synthesis in the pituitary and hypothalamus when T₃ binds to thyroid hormone receptors (TRs) that interact with the promoters of the genes for the TSH subunit and TRH. All TR isoforms are believed to be involved in the regulation of this endocrine axis, as evidenced by the massive dysregulation of TSH production in mice lacking all TR isoforms. However, the relative contributions of TR isoforms in the pituitary vs. the hypothalamus remain to be completely elucidated. Thus, to determine the relative contribution of pituitary expression of TR- in the regulation of the hypothalamic-pituitary-thyroid axis, we selectively impaired TR- function in TR-ß null mice (TR-ß^-/-) by pituitary restricted expression of a dominant negative TR-ß transgene harboring a 337T mutation. These animals exhibited 10-fold and 32-fold increase in T₄ and TSH concentrations, respectively. Moreover, the negative regulation of TSH by exogenous T₃ was completely absent and a paradoxical increase in TSH concentrations and TSH-ß mRNA was observed. In contrast, prepro-TRH expression levels in T₃-treated TR-ß^-/- were similar to levels observed in the 337/TR-ß^-/- mice, and ligand-independent activation of TSH in hypothyroid mice was equivalently impaired. Thus, isolated TR-ß deficiency in TRH paraventricular hypothalamic nucleus neurons and impaired function of all TRs in the pituitary recapitulate the baseline hormonal disturbances that characterize mice with complete absence of all TRs.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

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