Fraichard A, Chassande O, Plateroti M, Roux J P, Trouillas J, Dehay C, Legrand C, Gauthier K, Kedinger M, Malaval L, Rousset B, Samarut J
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Superieure de Lyon, UMR 49 CNRS, LA 913 INRA, France.
EMBO J. 1997 Jul 16;16(14):4412-20. doi: 10.1093/emboj/16.14.4412.
The diverse functions of thyroid hormones are thought to be mediated by two nuclear receptors, T3R alpha1 and T3R beta, encoded by the genes T3R alpha and T3R beta respectively. The T3R alpha gene also produces a non-ligand-binding protein T3R alpha2. The in vivo functions of these receptors are still unclear. We describe here the homozygous inactivation of the T3R alpha gene which abrogates the production of both T3R alpha1 and T3R alpha2 isoforms and that leads to death in mice within 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 hormone production, our data show that the T3R alpha gene products are involved in up-regulation of thyroid hormone production at weaning time. Thus, thyroid hormone production might be balanced through a positive T3R alpha and a negative T3R beta pathway. The abnormal phenotypes observed on the homozygous mutant mice strongly suggest that the T3R alpha 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 development.
甲状腺激素的多种功能被认为是由两种核受体介导的，即分别由T3Rα和T3Rβ基因编码的T3Rα1和T3Rβ。T3Rα基因还产生一种非配体结合蛋白T3Rα2。这些受体在体内的功能仍不清楚。我们在此描述T3Rα基因的纯合失活，它消除了T3Rα1和T3Rα2两种异构体的产生，并导致小鼠在出生后5周内死亡。出生2周后，纯合小鼠逐渐出现甲状腺功能减退，并表现出生长停滞。小肠和骨骼显示出明显延迟的成熟。与T3Rβ基因对甲状腺激素产生的负调节功能相反，我们的数据表明T3Rα基因产物在断奶时参与甲状腺激素产生的上调。因此，甲状腺激素的产生可能通过T3Rα的正向途径和T3Rβ的负向途径来平衡。在纯合突变小鼠上观察到的异常表型强烈表明，T3Rα基因对于依赖母体的幼崽转变为“成年”小鼠至关重要。这些数据确定了甲状腺激素在出生后发育过程中通过T3Rα途径的关键体内功能。
