THE T3R-ALPHA GENE ENCODING A THYROID-HORMONE RECEPTOR IS ESSENTIAL FOR POSTNATAL-DEVELOPMENT AND THYROID-HORMONE PRODUCTION

The diverse functions of thyroid hormones are thought to be mediated b y two nuclear receptors, T3R alpha 1 and T3R beta, encoded by the gene s T3R alpha and T3R beta respectively. The T3R alpha gene also produce s a non-ligand-binding protein T3R alpha 2. The in vivo functions of t hese receptors are still unclear, We describe here the homozygous inac tivation of the T3R alpha gene which abrogates the production of both T3R alpha 1 and T3R alpha 2 isoforms and that leads to death in mice w ithin 5 weeks after birth, After 2 weeks of life, the homozygous mice become progressively hypothyroidic and exhibit a growth arrest, Small intestine and bones showed a strongly delayed maturation, In contrast to the negative regulatory function of the T3R beta gene on thyroid ho rmone production, our data show that the T3R alpha gene products are i nvolved in up-regulation of thyroid hormone production at weaning time , Thus, thyroid hormone production might be balanced through a positiv e T3R alpha and a negative T3R beta pathway, The abnormal phenotypes o bserved on the homozygous mutant mice strongly suggest that the T3R al pha gene is essential for the transformation of a mother-dependent pup to an 'adult' mouse, These data define crucial in vivo functions for thyroid hormones through a T3R alpha pathway during post-natal develop ment.