Sexually dimorphic effects of forkhead box a2 (FOXA2) and uterine glands on decidualization and fetoplacental development
Glands of the uterus are essential for the establishment of pregnancy in mice, sheep and likely humans. 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 a considerable number of FOXA2-dependent GE-expressed genes. Adult FOXA2 conditional knockout (cKO; Ltf-iCre:Foxa2 flox) mice are infertile due to defective embryo implantation arising from a lack of leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin. 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 (GD) 8.5, the anti-mesometrial and mesometrial decidua transcriptome was noticeably altered in FOXA2 cKO mice. Viable fetuses were reduced in FOXA2 cKO mice on GDs 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. Overall design: The overall design employed studies of littermate control and conditional Foxa2 deleted dams on various days of gestation.