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Uterine kisspeptin receptor critically regulates epithelial estrogen receptor α transcriptional activity at the time of embryo implantation in a mouse model
Molecular Human Reproduction ( IF 4 ) Pub Date : 2021-09-10 , DOI: 10.1093/molehr/gaab060
Jennifer Schaefer 1, 2 , Angelos G Vilos 3 , George A Vilos 3 , Moshmi Bhattacharya 4, 5 , Andy V Babwah 1, 2, 5
Affiliation  

Embryo implantation failure is a major cause of infertility in women of reproductive age and a better understanding of uterine factors that regulate implantation is required for developing effective treatments for female infertility. This study investigated the role of the uterine kisspeptin receptor (KISS1R) in the molecular regulation of implantation in a mouse model. To conduct this study, a conditional uterine knockout (KO) of Kiss1r was created using the Pgr-Cre (progesterone receptor-CRE recombinase) driver. Reproductive profiling revealed that while KO females exhibited normal ovarian function and mated successfully to stud males, they exhibited significantly fewer implantation sites, reduced litter size and increased neonatal mortality demonstrating that uterine KISS1R is required for embryo implantation and a healthy pregnancy. Strikingly, in the uterus of Kiss1r KO mice on day 4 (D4) of pregnancy, the day of embryo implantation, KO females exhibited aberrantly elevated epithelial ERα (estrogen receptor α) transcriptional activity. This led to the temporal misexpression of several epithelial genes [Cftr (Cystic fibrosis transmembrane conductance regulator), Aqp5 (aquaporin 5), Aqp8 (aquaporin 8) and Cldn7 (claudin 7)] that mediate luminal fluid secretion and luminal opening. As a result, on D4 of pregnancy, the lumen remained open disrupting the final acquisition of endometrial receptivity and likely accounting for the reduction in implantation events. Our data clearly show that uterine KISS1R negatively regulates ERα signaling at the time of implantation, in part by inhibiting ERα overexpression and preventing detrimentally high ERα activity. To date, there are no reports on the regulation of ERα by KISS1R; therefore, this study has uncovered an important and powerful regulator of uterine ERα during early pregnancy.

中文翻译:

子宫吻肽素受体在小鼠模型胚胎植入时严格调节上皮雌激素受体α转录活性

胚胎植入失败是育龄妇女不孕的主要原因,需要更好地了解调节植入的子宫因素,才能开发出有效的女性不孕症治疗方法。本研究调查了子宫吻肽受体 (KISS1R) 在小鼠模型中植入的分子调控中的作用。为了进行这项研究,使用 Pgr-Cre(孕酮受体-CRE 重组酶)驱动程序创建了 Kiss1r 的条件性子宫敲除 (KO)。生殖分析显示,虽然 KO 雌性表现出正常的卵巢功能并成功与雄性雄性交配,但它们的植入部位显着减少,产仔数减少,新生儿死亡率增加,这表明子宫 KISS1R 是胚胎植入和健康怀孕所必需的。引人注目的是,在怀孕第 4 天(D4),胚胎植入当天,Kiss1r KO 小鼠的子宫中,KO 雌性表现出异常升高的上皮 ERα(雌激素受体 α)转录活性。这导致了介导管腔液分泌和管腔开口的几个上皮基因 [Cftr(囊性纤维化跨膜电导调节剂)、Aqp5(水通道蛋白 5)、Aqp8(水通道蛋白 8)和 Cldn7(密蛋白 7)] 的时间错误表达。因此,在妊娠第 4 天,管腔保持开放,破坏了子宫内膜容受性的最终获得,并可能导致着床事件减少。我们的数据清楚地表明,子宫 KISS1R 在植入时负调节 ERα 信号传导,部分是通过抑制 ERα 过表达和防止有害的高 ERα 活性。迄今为止,没有关于 KISS1R 调节 ERα 的报道;因此,本研究揭示了妊娠早期子宫 ERα 的一个重要而强大的调节剂。
更新日期:2021-09-10
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