A point mutation in the AF-2 domain of thyroid hormone receptor alpha1 expressed after CRE mediated recombination partially recapitulates hypothyroidism.
2007
Quignodon, Laure | Vincent, Séverine | Winter, Harald | Samarut, Jacques | Flamant, Frederic | Institut de Génomique Fonctionnelle de Lyon (IGFL) ; École normale supérieure de Lyon (ENS de Lyon) ; Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Centre National de la Recherche Scientifique (CNRS) | Laboratory of Molecular Neurobiology and Cell Biology of the Inner Ear ; Eberhard Karls Universität Tübingen = University of Tübingen | CASCADE CRESCENDO Ligue
Thyroid hormones act directly on transcription by binding to TRα1, TRβ1, TRβ2 nuclear receptors, regulating many aspects of post-natal development and homeostasis. To precisely analyze the implication of the widely expressed TRα1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRα1 coding sequence, which is expressed only after CRE/loxP mediated DNA recombination. The amino-acid change prevents interaction between TRα1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects post-natal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRβ1 and TRβ2 are predominantly expressed. Both respective abundance and intrinsic properties of TRα1 and TRβ1/2 seems to govern specificity of action.
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