Wen Luan, Shi Yun-Bo
Section on Molecular Morphogenesis, Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 18T, Rm. 106, Bethesda, Maryland, 20892, USA.
Dev Growth Differ. 2016 Jan;58(1):106-15. doi: 10.1111/dgd.12231. Epub 2015 Jul 28.
Thyroid hormone (TH) is critical for vertebrate postembryonic development, a period around birth in mammals when plasma TH levels are high. Interestingly, TH receptors (TRs), especially TRα, are expressed prior to the synthesis and secretion of zygotic TH, suggesting the existence of unliganded TR during development. However, the role of unliganded TR during mammalian development has been difficult to study, in part due to the relatively weak phenotype of TR knockout mice. Amphibian metamorphosis resembles postembryonic development in mammals and is controlled by TH via TRs. Like in mammals, TRα gene is highly activated and is the major TR expressed prior to the synthesis of endogenous TH. By using TALEN (transcriptional activator like effector nucleases)-mediated gene editing approach, we and others have now shown that unliganded TRα has two independent functions during Xenopus premetamorphosis, i.e. inhibiting growth rate and slowing development. Furthermore, molecular and transgenic studies have shown that unliganded TRα accomplishes these via the recruitment of histone deacetylase (HDAC)-containing corepressor complexes to repress the expression of TH-inducible genes.
甲状腺激素（TH）对脊椎动物胚胎后期发育至关重要，这一时期在哺乳动物中大约是出生前后，此时血浆TH水平较高。有趣的是，甲状腺激素受体（TRs），尤其是TRα，在合子TH合成和分泌之前就已表达，这表明在发育过程中存在未结合配体的TR。然而，由于TR基因敲除小鼠的表型相对较弱，未结合配体的TR在哺乳动物发育过程中的作用一直难以研究。两栖动物变态类似于哺乳动物的胚胎后期发育，由TH通过TRs进行调控。与哺乳动物一样，TRα基因被高度激活，是内源性TH合成之前表达的主要TR。通过使用TALEN（类转录激活因子效应物核酸酶）介导的基因编辑方法，我们和其他人现在已经表明，在非洲爪蟾变态前，未结合配体的TRα具有两个独立的功能，即抑制生长速率和延缓发育。此外，分子和转基因研究表明，未结合配体的TRα通过募集含组蛋白脱乙酰酶（HDAC）的共抑制复合物来实现这些功能，从而抑制TH诱导基因的表达。
