Thyroid hormones act directly on transcription by binding to TR1, TR1, TR2 nuclear receptors, regulating many aspects of post-natal development and homeostasis. To precisely analyze 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 post-natal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TR1 and TR2 are predominantly expressed. Both respective abundance and intrinsic properties of TR1 and TR1/2 seems to govern specificity of action.