Department of Biomedical Science, CHA University, Seongnam, Korea.
Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
FASEB J. 2018 Mar;32(3):1184-1195. doi: 10.1096/fj.201700854RR. Epub 2018 Jan 3.
The harmonized actions of ovarian E and progesterone (P) regulate the proliferation and differentiation of uterine cells in a spatiotemporal manner. Imbalances between these hormones often lead to infertility and gynecologic diseases. Whereas numerous factors that are involved in P signaling have been identified, few local factors that mediate E actions in the uterus have been revealed. Here, we demonstrate that estrogen induces the transcription factor, early growth response 1 ( Egr1), to fine-tune its actions in uterine epithelial cells (ECs) that are responsible for uterine receptivity for embryo implantation. In the presence of exogenous gonadotrophins, ovulation, fertilization, and embryonic development normally occur in Egr1 mice, but these animals experience the complete failure of embryo implantation with reduced artificial decidualization. Although serum levels of E and P were comparable between Egr1 and Egr1 mice on d 4 of pregnancy, aberrantly reduced levels of progesterone receptor in Egr1 uterine ECs caused enhanced E activity and impaired P response. Ultrastructural analyses revealed that Egr1 ECs are not fully able to provide proper uterine receptivity. Uterine mRNA landscapes in Egr1 mice revealed that EGR1 controls the expression of a subset of E-regulated genes. In addition, P signaling was unable to modulate estrogen actions, including those that are involved in cell-cycle progression, in ECs that were deficient in EGR1. Furthermore, primary coculture of Egr1 ECs with Egr1 stromal cells, and vice versa, supported the notion that Egr1 is required to modulate E actions on ECs to prepare the uterine environment for embryo implantation. In contrast to its role in ECs, loss of Egr1 in stroma significantly reduced stromal cell proliferation. Collectively, our results demonstrate that E induces EGR1 to streamline its actions for the preparation of uterine receptivity for embryo implantation in mice.-Kim, H.-R., Kim, Y. S., Yoon, J. A., Yang, S. C., Park, M., Seol, D.-W., Lyu, S. W., Jun, J. H., Lim, H. J., Lee, D. R., Song, H. Estrogen induces EGR1 to fine-tune its actions on uterine epithelium by controlling PR signaling for successful embryo implantation.
卵巢雌激素（E）和孕激素（P）的协调作用以时空方式调节子宫细胞的增殖和分化。这些激素之间的失衡常常导致不孕和妇科疾病。虽然已经确定了许多参与 P 信号转导的因素，但介导子宫中 E 作用的局部因素却很少被揭示。在这里，我们证明雌激素诱导转录因子早期生长反应因子 1（Egr1），以微调其在负责胚胎着床子宫接受性的子宫上皮细胞（ECs）中的作用。在外源促性腺激素存在的情况下，Egr1 小鼠的排卵、受精和胚胎发育通常正常发生，但这些动物在胚胎着床时完全失败，人工蜕膜化减少。尽管在妊娠第 4 天，Egr1 和 Egr1 小鼠的血清 E 和 P 水平相当，但 Egr1 子宫 ECs 中孕激素受体水平异常降低导致 E 活性增强和 P 反应受损。超微结构分析显示，Egr1 ECs 不能完全提供适当的子宫接受性。Egr1 小鼠的子宫 mRNA 图谱显示，EGR1 控制着一组 E 调节基因的表达。此外，P 信号转导不能调节 ECs 中雌激素的作用，包括那些参与细胞周期进展的作用，在 EGR1 缺乏的 ECs 中也是如此。此外，Egr1 ECs 与 Egr1 基质细胞的原代共培养，反之亦然，支持 Egr1 被需要来调节 ECs 中的 E 作用以准备胚胎着床的子宫环境的观点。与在 ECs 中的作用相反，基质中 Egr1 的缺失显著降低了基质细胞的增殖。总的来说，我们的结果表明，E 诱导 EGR1 来简化其在准备小鼠胚胎着床子宫接受性方面的作用。
