Forkhead box protein A2 (FOXA2) is a pioneer transcription factor important for epithelial budding and morphogenesis in different organs. It has been used as a specific marker for uterine glandular epithelial cells (GE). FOXA2 has close interactions with estrogen receptor α (ERα). ERα binding to Foxa2 gene in the uterus indicates its regulation of Foxa2. The intimate interactions between ERα and FOXA2 and their essential roles in early pregnancy led us to investigate the expression of FOXA2 in the female reproductive tract of pre-implantation epiERα^–/– (Esr1^fl/flWnt7a^Cre/+) mice, in which ERα is conditionally deleted in the epithelium of reproductive tract. In the oviduct, FOXA2 is detected in the ciliated epithelial cells of ampulla but absent in the isthmus of day 3.5 post-coitum (D3.5) Esr1^fl/fl control and epiERα^–/– mice. In the uterus, FOXA2 expression in the GE appears to be comparable between Esr1^fl/fl and epiERα^–/– mice. However, FOXA2 is upregulated in the D0.5 and D3.5 but not PND25-28 epiERα^–/– uterine luminal epithelial cells (LE). In the vagina, FOXA2 expression is low in the basal layer and increases toward the superficial layer of the D3.5 Esr1^fl/fl vaginal epithelium, but FOXA2 is detected in the basal, intermediate, and superficial layers, with the strongest FOXA2 expression in the intermediate layers of the D3.5 epiERα^–/^– vaginal epithelium. This study demonstrates that loss of ERα in LE and vaginal basal layer upregulates FOXA2 expression in these epithelial cells during early pregnancy. The mechanisms for epithelial cell-type specific regulation of FOXA2 by ERα remain to be elucidated.

Summary Sentence

FOXA2 is upregulated in the uterine luminal epithelial cells and vaginal basal epithelial cells of preimplantation epiERα^–/– (Esr1^fl/flWnt7a^Cre/+) mice that are deficient of ERα in the epithelium of the female reproductive tract (FRT).

Graphical Abstract