Gene expression profiling of Smad1/5 cKO and Acvr2a cKO mice

We generated mice with single or double conditional inactivation of SMAD1 and SMAD5 using progesterone receptor (PR) cre (Smad1flox/flox;Smad5flox/flox;Pgr-cre+/-, or "Smad1/5 cKO"). Female mice with single SMAD1 or SMAD5 deletion were subfertile, whereas Smad1/5 cKO were infertile and had no visible implantation sites at 4.5 days post-coitum (dpc), indicating functional redundancy of SMAD1 and SMAD5. Histological and molecular analyses of the Smad1/5 cKO uteri during pregnancy determined that the infertility was the result of impaired uterine receptivity. During the window of implantation, uteri of Smad1/5 cKO mice responded abnormally to estradiol (E2) and to progesterone (P4), retained luminal PR expression, and displayed cytoplasmic FOXO1 mis-localization. Furthermore, uteri of Smad1/5 cKO mice did not respond to an artificial decidual stimulus and the stroma failed to differentiate. To determine the cell surface receptor complex that controls BMP signaling during implantation, we generated mice with conditional deletion of Acvr2a and Acvr2b using Pgr-cre+/-. We determined that Acvr2b cKO females were subfertile, while Acvr2a cKOs were infertile and displayed a range of ovarian and uterine abnormalities, including endometrial and implantation defects that phenocopied those of Smad1/5 cKO mice. Transcriptomic profiling of the Smad1/5 cKO and Acvr2a cKO uterus showed that genes involved in epithelial cell remodeling and microvilli/ciliated cell function were overrepresented in both genotypes. These results demonstrate that BMP signals mediated via ACVR2A and SMAD1/5 control endometrial receptivity and embryo implantation by remodeling the apicobasal polarity of the epithelium during the window of implantation. Multiple group comparison我们利用孕酮受体（progesterone receptor, PR）重组酶系统，构建了SMAD1与SMAD5单基因或双基因条件性敲除的小鼠模型，基因型为Smad1^flox/flox;Smad5^flox/flox;Pgr-cre^+/-，简称“Smad1/5 cKO”。仅单敲除SMAD1或SMAD5的雌性小鼠生育能力低下，而Smad1/5 cKO小鼠则完全不育，且在交配后4.5天（days post-coitum, dpc）无可见的胚胎着床位点，这表明SMAD1与SMAD5存在功能冗余。 对妊娠期间Smad1/5 cKO小鼠子宫的组织学与分子分析显示，其不育表型源于子宫容受性受损。在着床窗口期内，Smad1/5 cKO小鼠子宫对雌二醇（estradiol, E2）与孕酮（progesterone, P4）的应答异常，仍保留腔上皮的PR表达，且出现叉头框O1（forkhead box O1, FOXO1）的细胞质错位分布。 此外，Smad1/5 cKO小鼠子宫无法对人工蜕膜化刺激产生应答，子宫基质细胞未能完成分化。为明确调控着床过程中骨形态发生蛋白（bone morphogenetic protein, BMP）信号通路的细胞表面受体复合物，我们利用Pgr-cre^+/-构建了Acvr2a与Acvr2b条件性敲除的小鼠模型。 研究发现，Acvr2b cKO雌性小鼠生育能力低下，而Acvr2a cKO小鼠则完全不育，且表现出一系列卵巢与子宫异常，包括与Smad1/5 cKO小鼠表型一致的子宫内膜与着床缺陷。 对Smad1/5 cKO与Acvr2a cKO小鼠子宫的转录组分析显示，两种基因型小鼠中均富集了大量参与上皮细胞重塑、微绒毛/纤毛细胞功能的基因。 上述结果证实，由ACVR2A与SMAD1/5介导的BMP信号通路，可通过重塑着床窗口期上皮细胞的顶基极性，调控子宫内膜容受性与胚胎着床。多组比较