Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, P.R. China.
Thyroid. 2021 Apr;31(4):692-702. doi: 10.1089/thy.2020.0410. Epub 2020 Nov 20.
Thyroid hormone (triiodothyronine [T3]) plays an important role in regulating vertebrate developmental, cellular, and metabolic processes via T3 receptor (TR). Liganded TR recruit coactivator complexes that include steroid receptor coactivators (SRC1, SRC2 or SRC3), which are histone acetyltransferases, to T3-responsive promoters. The functions of endogenous coactivators during T3-dependent mammalian adult organ development remain largely unclear, in part, due to the difficulty to access and manipulate late-stage embryos and neonates. We use metamorphosis as a model for postembryonic development in vertebrates. This process is controlled by T3, involves drastic changes in every organ/tissue, and can be easily manipulated. We have previously found that SRC3 was upregulated in the intestine during amphibian metamorphosis. To determine the function of endogenous SRC3 during intestinal remodeling, we have generated animals lacking a functional SRC3 gene and analyzed the resulting phenotype. Although removing SRC3 had no apparent effect on external development and animal gross morphology, the SRC3 (-/-) tadpoles displayed a reduction in the acetylation of histone H4 in the intestine compared with that in wild-type animals. Further, the expression of TR target genes was also reduced in SRC3 (-/-) tadpoles during intestinal remodeling. Importantly, SRC3 (-/-) tadpoles had inhibited/delayed intestinal remodeling during natural and T3-induced metamorphosis, including reduced adult intestinal stem cell proliferation and apoptosis of larval epithelial cells. Our results, thus, demonstrate that SRC3 is a critical component of the TR-signaling pathway during intestinal remodeling.
甲状腺激素（三碘甲状腺原氨酸[T3]）通过 T3 受体（TR）在调节脊椎动物发育、细胞和代谢过程中发挥重要作用。配体结合的 TR 招募包括类固醇受体共激活剂（SRC1、SRC2 或 SRC3）在内的共激活复合物，SRC3 是组蛋白乙酰转移酶，作用于 T3 反应性启动子。内源性共激活剂在 T3 依赖性哺乳动物成年器官发育中的功能在很大程度上仍不清楚，部分原因是难以接近和操纵晚期胚胎和新生儿。我们使用变态作为脊椎动物后生发育的模型。这个过程受 T3 控制，涉及每个器官/组织的剧烈变化，并且易于操作。我们之前发现 SRC3 在两栖动物变态过程中在肠道中上调。为了确定肠道重塑过程中内源性 SRC3 的功能，我们生成了缺乏功能性 SRC3 基因的动物，并分析了由此产生的表型。尽管去除 SRC3 对外部发育和动物大体形态没有明显影响，但 SRC3（-/-）蝌蚪的肠道中组蛋白 H4 的乙酰化水平比野生型动物降低。此外，在肠道重塑过程中，TR 靶基因的表达在 SRC3（-/-）蝌蚪中也降低。重要的是，SRC3（-/-）蝌蚪在自然和 T3 诱导的变态过程中抑制/延迟了肠道重塑，包括减少成年肠道干细胞的增殖和幼虫上皮细胞的凋亡。因此，我们的结果表明，SRC3 是肠道重塑过程中 TR 信号通路的关键组成部分。
