Increased Foxl2 Expression Alters Uterine Structures And Functions

The transcription factor forkhead box L2 (FOXL2) regulates sex differentiation and reproductive function. Elevated levels of this transcription factor have been observed in the diseases of the uterus, such as endometriosis. However, the impact of elevated FOXL2 expression on uterine physiology remains unknown. In order to determine the consequences of altered FOXL2 in the female reproductive axis, we generated mice with over-expression of FOXL2 (FOXL2(OE)) by crossing Foxl2(LsL/)(+) with the Progesterone receptor Pgr(cre) model. FOXL2(OE) uterus showed severe morphological abnormality including abnormal epithelial stratification, blunted adenogenesis, increased endometrial fibrosis, and disrupted myometrial morphology. In contrast, increasing FOXL2 levels specifically in uterine epithelium by crossing the Foxl2(LsL/)(+) with the lactoferrin Ltf(icre) mice resulted in the eFOXL2(OE) mice with uterine epithelial stratification but without defects in endometrial fibrosis and adenogenesis, demonstrating a role of the endometrial stroma in the uterine abnormalities of the FOXL2(OE) mice. Transcriptomic analysis of 12 weeks old Pgr(cre) and FOXL2(OE) uterus at diestrus stage showed multiple signaling pathways related with cellular matrix, wnt/beta-catenin, and altered cell cycle. Furthermore, we found FOXL2(OE) mice were sterile. The infertility was caused in part by a disruption of the hypophyseal ovarian axis resulting in an anovulatory phenotype. The FOXL2(OE) mice failed to show decidual responses during artificial decidualization in ovariectomized mice demonstrating the uterine contribution to the infertility phenotype. These data support that aberrantly increased FOXL2 expressions in the female reproductive tract can disrupt ovarian and uterine functions.