Embryo implantation in both humans and rodents is initiated by the attachment of a blastocyst to the uterine epithelium. For blastocyst attachment, the uterine epithelium needs to transform at both the structural and molecular levels first, and then initiate the interaction with trophectoderm. Any perturbation during this process will result in implantation failure or long-term adverse pregnancy outcomes. Endocrine steroid hormones, which function through nuclear receptors, combine with the local molecules produced by the uteri or embryo to facilitate implantation. The insulin-like growth factor (IGF) signaling has been reported to play a vital role during pregnancy. However, its physiological function during implantation remains elusive. This study revealed that mice with conditional deletion of Igf1r gene in uteri suffered from subfertility, mainly due to the disturbed uterine receptivity and abnormal embryo implantation. Mechanistically, we uncovered that in response to the nidatory estrogen on day 4 of pregnancy, the epithelial IGF1R, stimulated by the stromal cell-produced IGF1, facilitated epithelial STAT3 activation to modulate the epithelial depolarity. Furthermore, embryonic derived IGF2 could activate both the epithelial ERK1/2 and STAT3 signaling through IGF1R, which was critical for the transcription of Cox2 and normal attachment reaction. In brief, our data revealed that epithelial IGF1R was sequentially activated by the uterine stromal IGF1 and embryonic IGF2 to guarantee normal epithelium differentiation during the implantation process.

中文翻译：

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基质 IGF1 和胚胎 IGF2 对子宫上皮 IGF1R 的连续激活指导正常的子宫准备以进行胚胎植入

人类和啮齿动物的胚胎植入都是由胚泡附着在子宫上皮细胞开始的。对于囊胚附着，子宫上皮首先需要在结构和分子水平上进行转化，然后开始与滋养外胚层的相互作用。在此过程中的任何扰动都将导致植入失败或长期不良妊娠结局。通过核受体发挥作用的内分泌类固醇激素与子宫或胚胎产生的局部分子结合以促进植入。据报道，胰岛素样生长因子 (IGF) 信号传导在怀孕期间起着至关重要的作用。然而，其在植入过程中的生理功能仍然难以捉摸。这项研究揭示了条件性Igf1r缺失的小鼠子宫内的基因出现不孕症，主要是由于子宫容受性障碍和胚胎着床异常所致。从机制上讲，我们发现响应于妊娠第 4 天的结定性雌激素，由基质细胞产生的 IGF1 刺激的上皮 IGF1R 促进上皮 STAT3 激活以调节上皮去极性。此外，胚胎来源的 IGF2 可以通过 IGF1R 激活上皮 ERK1/2 和 STAT3 信号传导，这对于 Cox2 的转录和正常附着反应至关重要。简而言之，我们的数据显示上皮 IGF1R 依次被子宫基质 IGF1 和胚胎 IGF2 激活，以保证在植入过程中正常的上皮分化。