A point mutation in the activation function 2 domain of thyroid hormone receptor alpha1 expressed after CRE-mediated recombination partially recapitulates hypothyroidism.
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.
Quignodon
Laure
L
Institut de Génomique Fonctionnelle de Lyon, Université Lyon 1, Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5242-Institut National de la Recherche Agronomique 1288, F-69364 Lyon, France.
Vincent
Séverine
S
Winter
Harald
H
Samarut
Jacques
J
Flamant
Frédéric
F
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities; D005799:Genes, Dominant; D007037:Hypothyroidism / Q000235:genetics*; D019426:Integrases / Q000235:genetics; D007930:Leucine / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D011995:Recombination, Genetic; D013629:Tamoxifen / Q000494:pharmacology; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists* / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism
D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013629:Tamoxifen; D001120:Arginine; C045073:Cre recombinase; D019426:Integrases; D007930:Leucine