Growth, Development, and Intestinal Remodeling Occurs in the Absence of Thyroid Hormone Receptor α in Tadpoles of Xenopus tropicalis
Growth, Development, and Intestinal Remodeling Occurs in the Absence of Thyroid Hormone Receptor α in Tadpoles of Xenopus tropicalis
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DOI：
10.1210/en.2016-1955
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发表时间：
2017-06-01
期刊：
影响因子：
4.8
通讯作者：
Buchholz, Daniel R.
中科院分区：
文献类型：
--
作者：
Choi, Jinyoung;Ishizuya-Oka, Atsuko;Buchholz, Daniel R.
在所有脊椎动物的发育过程中，甲状腺激素受体（TRs）在血浆甲状腺激素（TH）水平达到峰值之前、期间和之后表达。之前，我们利用TR α敲除（TR α KO）青蛙的蝌蚪确定了未配体的TR α在基因抑制和发育时序中的作用。在这里，我们研究了配体TR α在自然和th诱导的变态过程中对生长、发育和肠道重塑的作用。破坏TR α对幼体生长影响不大，但在变态后，TR α KO幼体的生长比野生型（WT）幼体慢。当TH低或不存在时，TR α KO蝌蚪在整个前变态过程中发育得更快，尽管它们对外源TH的反应降低，但TR α KO蝌蚪不仅能够完成TH依赖性变态，而且比WT蝌蚪更早完成。与外部形态相反，TR α - KO蝌蚪的幼虫上皮细胞凋亡和成体肠重构细胞增殖延迟。此外，与WT幼崽相比，TR α KO的肠道长度没有完全收缩，进入管腔的肠道褶皱也较少。尽管TH靶基因TR β、Klf9和ST3在变质前表达水平较高，但这种延迟重塑仍会发生。此外，在自然和TH诱导的变态过程中，TH依赖性肠收缩的减少与TH反应基因表达的减少是一致的。与TR α缺失小鼠模型一样，TR α KO青蛙的生长和发育表型具有统计学意义，但令人惊讶的是，它们的生长和发育表型正常，存活和生育能力正常。
During development in all vertebrates, thyroid hormone receptors (TRs) are expressed before as well as during and after the peak in plasma thyroid hormone (TH) levels. Previously, we established a role for unliganded TR alpha in gene repression and developmental timing using tadpoles of TR alpha knockout (TR alpha KO) frogs. Here, we examined the role of liganded TR alpha on growth, development, and intestinal remodeling during natural and TH-induced metamorphosis. Disrupted TR alpha had little effect on growth during the larval period, but after metamorphosis, TR alpha KO juveniles grew more slowly than wild-type (WT) juveniles. TR alpha KO tadpoles developed faster throughout premetamorphosis when TH was low or absent, and despite their decreased responsivity to exogenous TH, TR alpha KO tadpoles not only were able to complete TH-dependent metamorphosis but also did so earlier than WT tadpoles. In contrast to external morphology, larval epithelial cell apoptosis and adult cell proliferation of intestinal remodeling were delayed in TR alpha KO tadpoles. Also, TR alpha KO intestines did not shrink in length to the full extent, and fewer intestinal folds into the lumen were present in TR alpha KO compared with WT juveniles. Such delayed remodeling occurred despite higher premetamorphic expression levels of TH target genes important for metamorphic progression-namely, TR beta, Klf9, and ST3. Furthermore, the decreased TH-dependent intestinal shrinkage was consistent with reduced TH response gene expression during natural and TH-induced metamorphosis. As in the TR alpha null mouse model, TR alpha KO frogs had statistically significant but surprisingly mild growth and development phenotypes with normal survival and fertility.