The fate of all species relies on successful reproduction. An essential event of human and rodent reproduction is successful embryo implantation into the uterine endometrium during early pregnancy. Failed early pregnancy is a major contributor to the globally rising rate of infertility. The uterus enters multiple transiently receptive states brought about by ovarian hormones estrogen (E2) and progesterone to facilitate early pregnancy events. A major component of uterine receptivity is the regulation of the uterine luminal epithelium (LE), to assist sperm transport for fertilization and establish maternal-embryo contact for implantation. Although, how E2 signaling regulates the uterine epithelial during early pregnancy remains a major knowledge gap. To alleviate this knowledge gap, we generated a conditional knockout mouse model targeting the main mediator of uterine estrogen signaling, estrogen receptor alpha (Esr1 / ERα), in the uterine epithelium (Esr1f/-Wnt7aCre/+; epiERα-/-). epiERα-/- females are infertile due to failed early pregnancy. When generating early pregnant mice, control females mated more quickly than epiERα-/- females. Comprehensive analysis revealed epiERα-/- mice had significantly longer plugging latency (time of male pairing to first copulatory plug) and disrupted reproductive cyclicity, discussed in chapter 2. In chapter 3, immunohistochemistry (IHC) revealed aberrant expression of the pioneering transcription factor Forkhead box protein A2 (FOXA2) in the early pregnant epiERα-/- LE, but not prepubertal epiERα-/- LE indicating epiERα is an important regulator of the uterine epithelial differentiation. To map the temporal E2-ERα-dependent transcriptomic changes in the early pregnant uterine epithelium we isolated and sequenced mRNA from control and epiERα-/- LE on day 0.5 post-coitum (D0.5) and D3.5. The resulting analysis in chapter 4 revealed major temporal differences in the D0.5 epiERα-/- LE involved in processes like cell signaling, uterine fluid homeostasis, and inflammation. We further investigated the aberrant increase of inflammatory signaling in the D0.5 epiERα-/- LE in chapter 5 where we found enhanced proinflammatory cytokines in the D0.5 epiERα-/- uterine tissue and to an overabundant number of neutrophils into the D0.5 epiERα-/- uterus. This dissertation provides novel information on the role of estrogen in the uterine epithelium during early pregnancy.
