O'Shea P J, Williams G R
Molecular Endocrinology Group, Division of Medicine and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
J Endocrinol. 2002 Dec;175(3):553-70. doi: 10.1677/joe.0.1750553.
Thyroid hormones exert a range of developmental and physiological actions in all vertebrates. Serum concentrations of L-thyroxine (T4) and 3,5,3 -L-triiodothyronine (T3) are maintained by a negative feedback loop involving T3-inhibition of hypothalamic thyrotrophin releasing hormone (TRH) and pituitary thyroid stimulating hormone (TSH) secretion, and by tissue specific and hormone-regulated expression of the three iodothyronine deiodinase enzymes that activate or metabolise thyroid hormones. T3 actions are mediated by two T3-receptors, TRalpha and TRbeta, which act as hormone-inducible transcription factors. The TRalpha (NR1A1) and TRbeta (NR1A2) genes encode mRNAs that are alternatively spliced to generate 9 mRNA isoforms (TRalpha1, alpha2, alpha3, Deltaalpha1, Deltaalpha2, beta1, beta2, beta3 and Deltabeta3), of which four (TRalpha1, alpha2, beta1 and beta2) are known to be expressed at the protein level in vivo. The numerous TR mRNAs are expressed widely in tissue- and developmental stage-specific patterns, although it is important to note that levels of mRNA expression may not correlate with receptor protein concentrations in individual tissues. The TRalpha2, alpha3, Deltaalpha1 and Deltaalpha2 transcripts encode proteins that fail to bind T3 in vitro. These non-binding isoforms, in addition to TRDeltabeta3 which does bind hormone, may act as dominant negative antagonists of the true T3-binding receptors in vitro, but their physiological functions and those of the TRbeta3 isoform have not been determined. In order to obtain a new understanding of the complexities of T3 action in vivo and the role of TRs during development, many mouse models of disrupted or augmented thyroid hormone signalling have been generated. The aim of this review is to provide a picture of the physiological actions of thyroid hormones by considering the phenotypes of these genetically modified mice.
甲状腺激素在所有脊椎动物中发挥着一系列发育和生理作用。血清L-甲状腺素（T4）和3,5,3'-L-三碘甲状腺原氨酸（T3）的浓度通过一个负反馈回路维持，该回路涉及T3对下丘脑促甲状腺激素释放激素（TRH）和垂体促甲状腺激素（TSH）分泌的抑制，以及通过三种碘甲状腺原氨酸脱碘酶的组织特异性和激素调节表达，这些酶可激活或代谢甲状腺激素。T3的作用由两种T3受体TRα和TRβ介导，它们作为激素诱导型转录因子发挥作用。TRα（NR1A1）和TRβ（NR1A2）基因编码的mRNA可选择性剪接产生9种mRNA异构体（TRα1、α2、α3、Δα1、Δα2、β1、β2、β3和Δβ3），其中四种（TRα1、α2、β1和β2）已知在体内会表达为蛋白质。众多的TR mRNA以组织和发育阶段特异性模式广泛表达，不过需要注意的是，mRNA表达水平可能与个别组织中的受体蛋白浓度并不相关。TRα2、α3、Δα1和Δα2转录本编码的蛋白质在体外无法结合T3。这些非结合异构体，除了能结合激素的TRΔβ3之外，在体外可能作为真正结合T3的受体的显性负性拮抗剂，但它们的生理功能以及TRβ3异构体的生理功能尚未确定。为了对T3在体内作用的复杂性以及TRs在发育过程中的作用有新的认识，人们构建了许多甲状腺激素信号传导被破坏或增强的小鼠模型。本综述的目的是通过考虑这些基因修饰小鼠的表型，来呈现甲状腺激素的生理作用。
