<i>FOXL2</i> is a Progesterone Target Gene in the Endometrium of Ruminants

• Main Authors: Caroline Eozenou, Audrey Lesage-Padilla, Vincent Mauffré, Gareth D. Healey, Sylvaine Camous, Philippe Bolifraud, Corinne Giraud-Delville, Daniel Vaiman, Takashi Shimizu, Akio Miyamoto, Iain Martin Sheldon, Fabienne Constant, Maëlle Pannetier, Olivier Sandra
• Format: Article
• Language: English
• Published: MDPI AG 2020-02-01
• Series: International Journal of Molecular Sciences
• Subjects: foxl2; endometrium; sheep; cattle; progesterone
• Online Access: https://www.mdpi.com/1422-0067/21/4/1478

Forkhead Box L2 (FOXL2) is a member of the FOXL class of transcription factors, which are essential for ovarian differentiation and function. In the endometrium, FOXL2 is also thought to be important in cattle; however, it is not clear how its expression is regulated. The maternal recognition of pregnancy signal in cattle, interferon-Tau, does not regulate <i>FOXL2</i> expression. Therefore, in the present study, we examined whether the ovarian steroid hormones that orchestrate implantation regulate <i>FOXL2</i> gene expression in ruminants. In sheep, we confirmed that <i>FOXL2</i> mRNA and protein was expressed in the endometrium across the oestrous cycle (day 4 to day 15 post-<i>oestrus</i>). Similar to the bovine endometrium, ovine <i>FOXL2</i> endometrial expression was low during the luteal phase of the oestrous cycle (4 to 12 days post-<i>oestrus</i>) and at implantation (15 days post-<i>oestrus</i>) while mRNA and protein expression significantly increased during the luteolytic phase (day 15 post-<i>oestrus</i> in cycle). In pregnant ewes, inhibition of progesterone production by trilostane during the day 5 to 16 period prevented the rise in progesterone concentrations and led to a significant increase of <i>FOXL2</i> expression in caruncles compared with the control group (1.4-fold, <i>p</i> &lt; 0.05). Ovariectomized ewes or cows that were supplemented with exogenous progesterone for 12 days or 6 days, respectively, had lower endometrial <i>FOXL2</i> expression compared with control ovariectomized females (sheep, mRNA, 1.8-fold; protein, 2.4-fold; cattle; mRNA, 2.2-fold; <i>p</i> &lt; 0.05). Exogenous oestradiol treatments for 12 days in sheep or 2 days in cattle did not affect <i>FOXL2</i> endometrial expression compared with control ovariectomized females, except at the protein level in both endometrial areas in the sheep. Moreover, treating bovine endometrial explants with exogenous progesterone for 48h reduced <i>FOXL2</i> expression. Using in vitro assays with COS7 cells we also demonstrated that progesterone regulates the <i>FOXL2</i> promoter activity through the progesterone receptor. Collectively, our findings imply that endometrial <i>FOXL2</i> is, as a direct target of progesterone, involved in early pregnancy and implantation.