Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation
Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation
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DOI：
10.1101/gad.13.10.1329
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发表时间：
1999-05-15
影响因子：
10.5
通讯作者：
Forrest, D
中科院分区：
文献类型：
--
作者：
Göthe, S;Wang, ZD;Forrest, D
甲状腺激素（T3）在发育和体内平衡中具有广泛的功能，尽管这种多样性产生的受体途径尚不清楚。T3受体TR α 1或TR β的缺失仅单独揭示了甲状腺功能减退症中出现的一小部分表型，这意味着必须存在其他途径。在这里，我们证明了缺乏TR α 1和TR β（TR α 1（-/-）β（-/-））的小鼠显示出一系列在单一受体缺陷小鼠中未发现的新表型，包括极度活跃的垂体-甲状腺轴，女性生育能力差，生长和骨成熟迟缓。这些结果表明，T3的主要作用是由TR α 1和TR β相互合作或相互替代的共同途径介导的。因此，改变TR α 1和TR β单独或组合使用的平衡有助于控制T3作用的扩展谱。没有证据表明TR α 1（-/-）β（-/-）小鼠组织中存在任何先前未鉴别的T3受体。与严重甲状腺功能减退症的衰弱症状相比，TR α 1（-/-）β（-/-）小鼠的总体表型较温和，缺乏所有已知的T3受体，表明激素与受体缺乏的不同后果。这些区别表明，T3受体的T3-独立的行动，证明以前在体外，可能是一个重要的功能在体内。
Thyroid hormone (T3) has widespread functions in development and homeostasis, although the receptor pathways by which this diversity arises are unclear. Deletion of the T3 receptors TR alpha 1 or TR beta individually reveals only a small proportion of the phenotypes that arise in hypothyroidism, implying that additional pathways must exist. Here, we demonstrate that mice lacking both TR alpha 1 and TR beta (TR alpha 1(-/-)beta(-/-)) display a novel array of phenotypes not found in single receptor-deficient mice, including an extremely hyperactive pituitary-thyroid axis, poor female fertility and retarded growth and bone maturation. These results establish that major T3 actions are mediated by common pathways in which TR alpha 1 and TR beta cooperate with or substitute for each other. Thus, varying the balance of use of TR alpha 1 and TR beta individually or in combination facilitates control of an extended spectrum of T3 actions. There was no evidence for any previously unidentified T3 receptors in TR alpha 1(-/-)beta(-/-) mouse tissues. Compared to the debilitating symptoms of severe hypothyroidism, the milder overall phenotype of TR alpha 1(-/-)beta(-/-) mice, lacking all known T3 receptors, indicates divergent consequences for hormone versus receptor deficiency. These distinctions suggest that T3-independent actions of T3 receptors, demonstrated previously in vitro, may be a significant function in vivo.