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A Point Mutation in the Activation Function 2 Domain of Thyroid Hormone Receptor 1 Expressed after CRE-Mediated Recombination Partially Recapitulates Hypothyroidism

Institut de Génomique Fonctionnelle de Lyon (L.Q., S.V., J.S., F.F.), Université Lyon 1, Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche (UMR), Centre National de la Recherche Scientifique 5242-Institut National de la Recherche Agronomique 1288, F-69364 Lyon, France; and University of Tübingen (H.W.), Tübingen Hearing Research Centre, Laboratory of Molecular Neurobiology, 72074 Tübingen, Germany

Address all correspondence and requests for reprints to: Frédéric Flamant, Institut de Génomique Fonctionnelle, Ecole Normale Supérieure de Lyon, 46 allée d’Italie, 69364 Lyon Cedex 07, France. E-mail: Frederic.Flamant{at}ens-lyon.fr.

Thyroid hormones act directly on transcription by binding to TR1, TRß1, and TRß2 nuclear receptors, regulating many aspects of postnatal development and homeostasis. To analyze precisely the implication of the widely expressed TR1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TR1 coding sequence, which is expressed only after CRE/loxP-mediated DNA recombination. The amino acid change prevents interaction between TR1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects postnatal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRß1 and TRß2 are predominantly expressed. Both respective abundance and intrinsic properties of TR1 and TRß1/2 seem to govern specificity of action.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Coregulators:   SRC-1  |  GRIP1  |  NCOR

Ligands:   Thyroid hormone