Grimaldi Alexis, Buisine Nicolas, Miller Thomas, Shi Yun-Bo, Sachs Laurent M
Muséum National d'Histoire Naturelle, Dépt. Régulation Développement et Diversité Moléculaire, UMR7221 CNRS, Evolution des Régulations Endocriniennes, Section on thyroid hormone receptor function and mechanism of action, 57 rue Cuvier, 75231 Paris cedex 05, France.
Biochim Biophys Acta. 2013 Jul;1830(7):3882-92. doi: 10.1016/j.bbagen.2012.04.020. Epub 2012 Apr 28.
Thyroid hormone (TH) receptor (TR) plays critical roles in vertebrate development. However, the in vivo mechanism of TR action remains poorly explored.
Frog metamorphosis is controlled by TH and mimics the postembryonic period in mammals when high levels of TH are also required. We review here some of the findings on the developmental functions of TH and TR and the associated mechanisms obtained from this model system.
A dual function model for TR in Anuran development was proposed over a decade ago. That is, unliganded TR recruits corepressors to TH response genes in premetamorphic tadpoles to repress these genes and prevent premature metamorphic changes. Subsequently, when TH becomes available, liganded TR recruits coactivators to activate these same genes, leading to metamorphic changes. Over the years, molecular and genetic approaches have provided strong support for this model. Specifically, it has been shown that unliganded TR recruits histone deacetylase containing corepressor complexes during larval stages to control metamorphic timing, while liganded TR recruits multiple histone modifying and chromatin remodeling coactivator complexes during metamorphosis. These complexes can alter chromatin structure via nucleosome position alterations or eviction and histone modifications to contribute to the recruitment of transcriptional machinery and gene activation.
The molecular mechanisms of TR action in vivo as revealed from studies on amphibian metamorphosis are very likely applicable to mammalian development as well. These findings provide a new perspective for understanding the diverse effects of TH in normal physiology and diseases caused by TH dysfunction. This article is part of a Special Issue entitled Thyroid hormone signalling.
甲状腺激素（TH）受体（TR）在脊椎动物发育中起关键作用。然而，TR作用的体内机制仍未得到充分探索。
青蛙变态受TH控制，模拟哺乳动物胚胎后期，此时也需要高水平的TH。我们在此综述了从该模型系统中获得的关于TH和TR的发育功能及相关机制的一些发现。
十多年前提出了TR在无尾目动物发育中的双功能模型。即，未结合配体的TR在变态前的蝌蚪中募集共抑制因子至TH反应基因，以抑制这些基因并防止过早的变态变化。随后，当有TH时，结合配体的TR募集共激活因子来激活这些相同的基因，从而导致变态变化。多年来，分子和遗传方法为该模型提供了有力支持。具体而言，已表明未结合配体的TR在幼虫阶段募集含组蛋白去乙酰化酶的共抑制因子复合物以控制变态时间，而结合配体的TR在变态过程中募集多种组蛋白修饰和染色质重塑共激活因子复合物。这些复合物可通过核小体位置改变或驱逐以及组蛋白修饰来改变染色质结构，以促进转录机制的募集和基因激活。
从两栖动物变态研究中揭示的TR在体内作用的分子机制很可能也适用于哺乳动物发育。这些发现为理解TH在正常生理学中的多种作用以及由TH功能障碍引起的疾病提供了新的视角。本文是名为“甲状腺激素信号传导”的特刊的一部分。
