Glands of the uterus are essential for pregnancy establishment. Forkhead box A2 (FOXA2) is expressed specifically in the glands of the uterus and a critical regulator of glandular epithelium (GE) differentiation, development, and function. Mice with a conditional deletion of FOXA2 in the adult uterus, created using the lactotransferrin iCre (Ltf-iCre) model, have a morphologically normal uterus with glands, but lack FOXA2-dependent GE-expressed genes, such as leukemia inhibitory factor (LIF). Adult FOXA2 conditional knockout (cKO; Ltf^iCre/+Foxa2^f/f) mice are infertile due to defective embryo implantation arising from a lack of LIF, a critical implantation factor of uterine gland origin. However, intraperitoneal injections of LIF can initiate embryo implantation in the uterus of adult FOXA2 cKO mice with pregnancies maintained to term. Here, we tested the hypothesis that FOXA2-regulated genes in the uterine glands impact development of the decidua, placenta, and fetus. On gestational day 8.5, the antimesometrial and mesometrial decidua transcriptome was noticeably altered in LIF-replaced FOXA2 cKO mice. Viable fetuses were reduced in FOXA2 cKO mice on gestational days 12.5 and 17.5. Sex-dependent differences in fetal weight, placenta histoarchitecture, and the placenta and metrial gland transcriptome were observed between control and FOXA2 cKO mice. The transcriptome of the placenta with a female fetus was considerably more altered than the placenta with a male fetus in FOXA2 cKO dams. These studies reveal previously unrecognized sexually dimorphic effects of FOXA2 and uterine glands on fetoplacental development with potential impacts on offspring health into adulthood.

子宫腺对于建立怀孕至关重要。叉头盒A2（FOXA2）在子宫腺体中特别表达，是腺上皮（GE）分化，发育和功能的关键调节剂。使用乳铁传递蛋白iCre（Ltf-iCre）模型创建的在成年子宫中有条件删除FOXA2的小鼠，子宫形态学正常，但具有腺体，但是缺乏FOXA2依赖性的GE表达基因，例如白血病抑制因子（LIF） 。成人FOXA2有条件淘汰赛（cKO; Ltf ^{iCre / +} Foxa2 ^{f / f}）由于缺乏LIF（子宫腺起源的关键植入因子）导致的胚胎植入缺陷，小鼠无法生育。但是，腹膜内注射LIF可以启动成年FOXA2 cKO小鼠子宫的胚胎植入，并维持妊娠至足月。在这里，我们检验了以下假设：子宫腺中FOXA2调控的基因影响蜕膜，胎盘和胎儿的发育。在妊娠第8.5天，在LIF替代的FOXA2 cKO小鼠中，蜕膜和蜕膜蜕膜组显着改变。FOXA2 cKO小鼠在妊娠第12.5天和17.5天存活的胎儿减少。在对照组和FOXA2 cKO小鼠之间观察到胎儿体重，胎盘组织结构以及胎盘和子宫腺转录组的性别依赖性差异。在FOXA2 cKO大坝中，具有雌性胎儿的胎盘的转录组的变化比具有雄性胎儿的胎盘的变化大得多。这些研究揭示了FOXA2和子宫腺对胎儿胎盘发育的前所未有的性双态性影响，并可能影响到成年后代的健康。