A Point Mutation in the Activation Function 2 Domain of Thyroid Hormone Receptor α1 Expressed after CRE-Mediated Recombination Partially Recapitulates Hypothyroidism

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 21; no. 10; pp. 2350 - 2360
• Main Authors: Quignodon, Laure, Vincent, Séverine, Winter, Harald, Samarut, Jacques, Flamant, Frédéric
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01.10.2007; Oxford University Press
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2007-0176

Thyroid hormones act directly on transcription by binding to TRα1, TRβ1, and TRβ2 nuclear receptors, regulating many aspects of postnatal development and homeostasis. To analyze precisely 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 postnatal 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 seem to govern specificity of action.