Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, China.
Reproductive Medicine Centre, Taihe Hospital, Hubei University of Medicine, 32 South Renming Road, Shiyan, Hubei 442000, China.
Curr Mol Med. 2020;20(8):633-642. doi: 10.2174/1566524020666200225115526.
Recent studies have demonstrated that endometrial DNA methylation is essential for embryo implantation during early pregnancy. Dnmt3a is one of the key enzymes for DNA methylation and could be expressed in the endometrium regularly at this stage.
In this study, we conditionally ablated uterine Dnmt3a using progesterone receptor-cre (Pgrcre) to define the physiological roles of Dnmt3a in female reproduction.
We found that ovarian function was not apparently altered and the number of embryo implantation sites in Dnmt3a Pgr (cKO) was not significantly varied during early pregnancy. Western blotting and immunohistochemistry results showed no difference in expression or location of the estrogen receptor α (ERα) and mucin 1 (Muc1), the marker of uterine receptivity. Although the expression of decidual markers, matrix metalloproteinase-2 (Mmp2), matrix metalloproteinase-9(Mmp9), and bone morphogenetic protein-2 (Bmp2), was slightly decreased in Dnmt3a cKO females, the gross morphology of mice uteri during decidualization was not significantly influenced. In the artificial induction of the decidualization model, there was also no remarkable difference in visually observed morphology or uterine weight in Dnmt3a cKO. Lastly, a continuous breeding study showed that the fertility of Dnmt3a cKO female mice was not strikingly altered.
Overall, these results demonstrated that although some decidual markers are expressed abnormally, conditional knockout of Dnmt3a in the uterus did not significantly affect the endometrial function during embryo implantation; the embryo could implant into the endometrium normally.
最近的研究表明,子宫内膜 DNA 甲基化对于妊娠早期胚胎着床至关重要。Dnmt3a 是 DNA 甲基化的关键酶之一,在这个阶段可能会在子宫内膜中规律表达。
本研究通过孕激素受体-cre(Pgrcre)条件性敲除子宫 Dnmt3a,以明确 Dnmt3a 在女性生殖中的生理作用。
我们发现卵巢功能并未明显改变,Dnmt3a Pgr(cKO)组胚胎着床部位数量在妊娠早期也无明显差异。Western 印迹和免疫组化结果显示,雌激素受体 α(ERα)和黏蛋白 1(Muc1)的表达或位置没有差异,Muc1 是子宫容受性的标志物。尽管 Dnmt3a cKO 雌性小鼠的蜕膜化标记物基质金属蛋白酶-2(Mmp2)、基质金属蛋白酶-9(Mmp9)和骨形态发生蛋白-2(Bmp2)的表达略有下降,但蜕膜化小鼠子宫的大体形态并未受到显著影响。在人工诱导蜕膜化模型中,Dnmt3a cKO 组的子宫形态或重量也没有明显差异。最后,连续繁殖研究表明,Dnmt3a cKO 雌性小鼠的生育力并未明显改变。
总之,这些结果表明,尽管一些蜕膜化标记物表达异常,但子宫中 Dnmt3a 的条件性敲除并未显著影响胚胎着床期间的子宫内膜功能;胚胎可以正常着床到子宫内膜中。