The coregulator, repressor of estrogen receptor activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization.
The coregulator, repressor of estrogen receptor activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization.
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DOI：
10.1210/en.2012-2026
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发表时间：
2013-02
期刊：
影响因子：
4.8
通讯作者：
Yuechao Zhao;Sung-Hee Park;M. Bagchi;Robert N. Taylor;B. Katzenellenbogen
中科院分区：
文献类型：
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作者：
Yuechao Zhao;Sung-Hee Park;M. Bagchi;Robert N. Taylor;B. Katzenellenbogen
成功着床和维持妊娠需要子宫内膜间质细胞转化为不同的蜕膜细胞。虽然已知雌激素和孕激素(P4)受体在蜕膜化过程中是必不可少的，但类固醇受体辅助调节因子在这一过程中的作用仍然很大程度上尚不清楚。在这项研究中，我们确定了雌激素受体活性抑制因子(REA)在体外人子宫内膜间质细胞(HESCs)和体内小鼠子宫蜕膜化过程中的关键作用。我们的研究表明，随着hESC蜕膜化的进行，REA的水平通常会下降到一半，而转基因杂合基因敲除小鼠子宫中REA的减少或hESC中REA的小干扰RNA敲除在时间上加速并强烈促进了分化过程，这表现在细胞形态的变化和包括P4受体在内的蜕膜化生物标志物的表达增加。在体外培养的人胚胎干细胞与雌二醇、P4和8-溴-cAMP一起培养10天后的结果反映了REA杂合缺失转基因小鼠的蜕膜化反应增强的观察。重要的是，基因表达和免疫组织化学分析揭示了Janus激酶/信号转导和转录激活因子途径的多个组成部分的变化，包括信号转导和转录激活因子3和IL-11的显著上调，以及蜕膜形成的主要调节因子，以及几个细胞因子信号转导抑制因子家族成员的下调。研究结果强调，REA在生理上抑制子宫内膜间质细胞蜕膜化，控制蜕膜化的时间和大小，以实现子宫分化与同时胚胎发育的适当协调，这对着床和最佳生育至关重要。
Successful implantation and maintenance of pregnancy require the transformation of uterine endometrial stromal cells into distinct decidualized cells. Although estrogen and progesterone (P4) receptors are known to be essential for decidualization, the roles of steroid receptor coregulators in this process remain largely unknown. In this study, we have established a key role for the coregulator, repressor of estrogen receptor activity (REA), in the decidualization of human endometrial stromal cells (hESCs) in vitro and of the mouse uterus in vivo. Our studies revealed that the level of REA normally decreases to half as hESC decidualization proceeds and that uterine reduction of REA in transgenic heterozygous knockout mice or small interfering RNA knockdown of REA in hESC temporally accelerated and strongly enhanced the differentiation process, as indicated by changes in cell morphology and increased expression of biomarkers of decidualization, including P4 receptor. Findings in hESC cultured in vitro with estradiol, P4, and 8-bromo-cAMP over a 10-day period mirrored observations of enhanced decidualization response in transgenic mice with heterozygous deletion of REA. Importantly, gene expression and immunohistochemical analyses revealed changes in multiple components of the Janus kinase/signal transducer and activator of transcription pathway, including marked up-regulation of signal transducer and activator of transcription 3 and IL-11, master regulators of decidualization, and the down-regulation of several suppressor of cytokine signaling family members, upon reduction of REA. The findings highlight that REA physiologically restrains endometrial stromal cell decidualization, controlling the timing and magnitude of decidualization to enable proper coordination of uterine differentiation with concurrent embryo development that is essential for implantation and optimal fertility.