Journal article
Dominant Inhibition of Thyroid Hormone Action Selectively in the Pituitary of Thyroid Hormone Receptor-β Null Mice Abolishes the Regulation of Thyrotropin by Thyroid Hormone
Molecular endocrinology (Baltimore, Md.), Vol.17(9), pp.1767-1776
09/01/2003
DOI: 10.1210/me.2003-0109
PMID: 12819298
Abstract
Abstract 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-α in the regulation of the hypothalamic-pituitary-thyroid axis, we selectively impaired TR-α function in TR-β null mice (TR-β−/−) by pituitary restricted expression of a dominant negative TR-β transgene harboring a Δ337T 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-β mRNA was observed. In contrast, prepro-TRH expression levels in T3-treated TR-β−/− were similar to levels observed in the Δ337/TR-β−/− mice, and ligand-independent activation of TSH in hypothyroid mice was equivalently impaired. Thus, isolated TR-β 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.
Details
- Title: Subtitle
- Dominant Inhibition of Thyroid Hormone Action Selectively in the Pituitary of Thyroid Hormone Receptor-β Null Mice Abolishes the Regulation of Thyrotropin by Thyroid Hormone
- Creators
- E. Dale Abel - Division of Endocrinology (E.D.A.), Metabolism and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112Egberto G Moura - Departamento de Ciencias Fisiologicas (E.G.M.), Instituto de Biologia, Universidade do Estado do Rio de Janeiro, 20550-030 Rio de Janeiro, BrazilRexford S Ahima - Division of Endocrinology (R.S.A.), Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104Angel Campos-Barros - Department of Human Genetics (A.C.-B., D.F.), Mount Sinai School of Medicine, New York, New York 10029Carmen C Pazos-Moura - 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, BrazilMary-Ellen Boers - Division of Endocrinology and Metabolism (M.-E.B., H.C.K.), Beth Israel Deaconess Medical Center, Boston Massachusetts 02215Helen C Kaulbach - Division of Endocrinology and Metabolism (M.-E.B., H.C.K.), Beth Israel Deaconess Medical Center, Boston Massachusetts 02215Douglas Forrest - Department of Human Genetics (A.C.-B., D.F.), Mount Sinai School of Medicine, New York, New York 10029Fredric E Wondisford - Section of Endocrinology and Metabolism (F.E.W.), Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637
- Resource Type
- Journal article
- Publication Details
- Molecular endocrinology (Baltimore, Md.), Vol.17(9), pp.1767-1776
- DOI
- 10.1210/me.2003-0109
- PMID
- 12819298
- ISSN
- 0888-8809
- eISSN
- 1944-9917
- Language
- English
- Date published
- 09/01/2003
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024524902771
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