Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Biol Reprod. 2020 Oct 29;103(5):951-965. doi: 10.1093/biolre/ioaa143.
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 (FOXL2OE) by crossing Foxl2LsL/+ with the Progesterone receptor Pgrcre model. FOXL2OE 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 Foxl2LsL/+ with the lactoferrin Ltficre mice resulted in the eFOXL2OE 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 FOXL2OE mice. Transcriptomic analysis of 12 weeks old Pgrcre and FOXL2OE uterus at diestrus stage showed multiple signaling pathways related with cellular matrix, wnt/β-catenin, and altered cell cycle. Furthermore, we found FOXL2OE mice were sterile. The infertility was caused in part by a disruption of the hypophyseal ovarian axis resulting in an anovulatory phenotype. The FOXL2OE 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.
叉头框转录因子 L2（FOXL2）调节性别分化和生殖功能。在子宫内膜异位症等子宫疾病中观察到这种转录因子水平升高。然而，升高的 FOXL2 表达对子宫生理学的影响尚不清楚。为了确定雌性生殖轴中改变的 FOXL2 的后果，我们通过将 Foxl2LsL/+与孕激素受体 Pgrcre 模型杂交，生成 FOXL2 过表达（FOXL2OE）的小鼠。FOXL2OE 子宫表现出严重的形态异常，包括上皮分层异常、腺形成减弱、子宫内膜纤维化增加和子宫肌层形态破坏。相比之下，通过将 Foxl2LsL/+与乳铁蛋白 Ltficre 小鼠杂交，特异性增加子宫上皮中的 FOXL2 水平，导致 eFOXL2OE 小鼠出现子宫上皮分层，但没有子宫内膜纤维化和腺形成缺陷，表明子宫内膜基质在 FOXL2OE 小鼠的子宫异常中起作用。在动情期第 12 周时，对 Pgrcre 和 FOXL2OE 子宫进行转录组分析，显示与细胞基质、Wnt/β-catenin 和细胞周期改变相关的多个信号通路。此外，我们发现 FOXL2OE 小鼠不育。不孕的部分原因是垂体卵巢轴的破坏导致无排卵表型。在卵巢切除的小鼠中进行人工蜕膜化时，FOXL2OE 小鼠未能表现出蜕膜反应，这表明子宫对不孕表型的贡献。这些数据支持女性生殖道中异常增加的 FOXL2 表达可破坏卵巢和子宫功能。
