A point mutation in the activation function 2 domain of thyroid hormone receptor α1 expressed after CRE-mediated recombination partially recapitulates hypothyroidism

Thyroid hormones act directly on transcription by binding to TR alpha 1, TR beta 1, and TR beta 2 nuclear receptors, regulating many aspects of postnatal development and homeostasis. To analyze precisely the implication of the widely expressed TR alpha 1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TR alpha 1 coding sequence, which is expressed only after CRE/ loxP- mediated DNA recombination. The amino acid change prevents interaction between TR alpha 1 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 TR beta 1 and TR beta 2 are predominantly expressed. Both respective abundance and intrinsic properties of TR alpha 1 and TR beta 1/ 2 seem to govern specificity of action.