title: TR alpha 2 exerts dominant negative effects on hypothalamic Trh transcription in vivo.
abstract: Mammalian thyroid hormone receptors (TRs) have multiple isoforms, including the bona fide receptors that bind T3 (TRα1, TRβ1 and TRβ2) and a non-hormone-binding variant, TRα2. Intriguingly, TRα2 is strongly expressed in the brain, where its mRNA levels exceed those of functional TRs. Ablation of TRα2 in mice results in over-expression of TRα1, and a complex phenotype with low levels of free T3 and T4, without elevated TSH levels, suggesting an alteration in the negative feedback at the hypothalamic-pituitary level. As the hypothesis of a potential TRH response defect has never been tested, we explored the functional role of TRα2 in negative feedback on transcription of hypothalamic thyrotropin, Trh. The in vivo transcriptional effects of TRα2 on hypothalamic Trh were analysed using an in vivo reporter gene approach. Effects on Trh-luc expression were examined to that of two, T3 positively regulated genes used as controls. Applying in vivo gene transfer showed that TRα2 over-expression in the mouse hypothαlamus abrogates T3-dependent repression of Trh and T3 activation of positively regulated promoters, blocking their physiological regulation. Surprisingly, loss of function studies carried out by introducing a shTRα2 construct in the hypothalamus also blocked physiological T3 dependent regulation. Thus, modulating hypothalamic TRα2 expression by either gain or loss of function abrogated T3 dependent regulation of Trh transcription, producing constant transcriptional levels insensitive to feedback. This loss of physiological regulation was reflected at the level of the endogenous Trh gene, were gain or loss of function held mRNA levels constant. These results reveal the as yet undescribed dominant negative role of TRα2 over TRα1 effect on hypothalamic Trh transcription.
authors.affiliation: Laboratoire de Génétique, Immunologie et Pathologies Humaines, Département de Biologie, Faculté des Sciences de Tunis, CAMPUS, Université Tunis El Manar, Tunis, Tunisie; UMR CNRS 7221, Evolution des Régulations Endocriniennes, Department Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Hajer
authors.initials: H
authors.lastname: Guissouma
authors.affiliation: UMR CNRS 7221, Evolution des Régulations Endocriniennes, Department Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Rym
authors.initials: R
authors.lastname: Ghaddab-Zroud
authors.affiliation: UMR CNRS 7221, Evolution des Régulations Endocriniennes, Department Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Seugnet
authors.affiliation: UMR CNRS 7221, Evolution des Régulations Endocriniennes, Department Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Decherf
authors.affiliation: UMR CNRS 7221, Evolution des Régulations Endocriniennes, Department Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Demeneix
authors.affiliation: UMR CNRS 7221, Evolution des Régulations Endocriniennes, Department Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Marie-Stéphanie
authors.initials: MS
authors.lastname: Clerget-Froidevaux
mesh_terms: D000818:Animals; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D037021:Thyroid Hormone Receptors alpha
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