Thyroid hormones act directly on transcription by binding to TRalpha1, TRbeta1, and TRbeta2 nuclear receptors, regulating many aspects of postnatal development and homeostasis. To analyze precisely the implication of the widely expressed TRalpha1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRalpha1 coding sequence, which is expressed only after CRE/loxP-mediated DNA recombination. The amino acid change prevents interaction between TRalpha1 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 TRbeta1 and TRbeta2 are predominantly expressed. Both respective abundance and intrinsic properties of TRalpha1 and TRbeta1/2 seem to govern specificity of action.