BACKGROUND In mammals, early pregnancy is a critical vulnerable period during which complications may arise, including pregnancy failure. Establishment of a maternal endometrial acceptance phenotype is a prerequisite for semiheterogeneous embryo implantation, comprising the rate-limiting step of early pregnancy. METHODS Confocal fluorescence, immunohistochemistry and western blot for nuclear and cytoplasmic protein were used to examine the activation of yes-associated protein (YAP) in uterine tissue and primary endometrial cells. The target binding between miR16a and YAP was verified by dual-luciferase reporter gene assay. The mouse pregnancy model and pseudopregnancy model were used to investigate the role of YAP in the maternal uterus during early pregnancy in vivo. RESULTS We showed that YAP translocates into the nucleus in the endometrium of cattle and mice during early pregnancy. Mechanistically, YAP acts as a mediator of ECM rigidity and cell density, which requires the actomyosin cytoskeleton and is partially dependent on the Hippo pathway. Furthermore, we found that the soluble factor IFNτ, which is a ruminant pregnancy recognition factor, also induced activation of YAP by reducing the expression of miR-16a. CONCLUSIONS This study revealed that activation of YAP is necessary for early pregnancy in bovines because it induced cell proliferation and established an immunosuppressive local environment that allowed conceptus implantation into the uterine epithelium.

中文翻译：

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子宫内膜细胞外基质刚性和 IFNτ 通过激活 YAP 确保早孕的建立

背景在哺乳动物中，早孕是一个关键的脆弱时期，在此期间可能出现并发症，包括妊娠失败。建立母体子宫内膜接受表型是半异质胚胎着床的先决条件，包括早期妊娠的限速步骤。方法采用共聚焦荧光、免疫组织化学和免疫印迹法检测细胞核和细胞质蛋白，检测子宫组织和原代子宫内膜细胞中 yes 相关蛋白 (YAP) 的激活。通过双荧光素酶报告基因检测验证了 miR16a 和 YAP 之间的靶标结合。使用小鼠妊娠模型和假妊娠模型在体内研究YAP在妊娠早期在母体子宫中的作用。结果我们发现，在妊娠早期，YAP 易位到牛和小鼠子宫内膜的细胞核中。从机制上讲，YAP 充当 ECM 刚性和细胞密度的介质，这需要肌动球蛋白细胞骨架并且部分依赖于 Hippo 通路。此外，我们发现作为反刍动物妊娠识别因子的可溶性因子 IFNτ 也通过降低 miR-16a 的表达来诱导 YAP 的激活。结论 本研究表明，YAP 的激活是牛早期妊娠所必需的，因为它诱导细胞增殖并建立了一个免疫抑制的局部环境，允许胚胎植入子宫上皮。这需要肌动球蛋白细胞骨架并且部分依赖于 Hippo 途径。此外，我们发现作为反刍动物妊娠识别因子的可溶性因子 IFNτ 也通过降低 miR-16a 的表达来诱导 YAP 的激活。结论 本研究表明，YAP 的激活是牛早期妊娠所必需的，因为它诱导细胞增殖并建立了一个免疫抑制的局部环境，允许胚胎植入子宫上皮。这需要肌动球蛋白细胞骨架并且部分依赖于 Hippo 途径。此外，我们发现作为反刍动物妊娠识别因子的可溶性因子 IFNτ 也通过降低 miR-16a 的表达来诱导 YAP 的激活。结论 本研究表明，YAP 的激活是牛早期妊娠所必需的，因为它诱导细胞增殖并建立了一个免疫抑制的局部环境，允许胚胎植入子宫上皮。