FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

Abstract

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 FOXL2 expression. Therefore, in the present study, we examined whether the ovarian steroid hormones that orchestrate implantation regulate FOXL2 gene expression in ruminants. In sheep, we confirmed that FOXL2 mRNA and protein was expressed in the endometrium across the oestrous cycle (day 4 to day 15 post-oestrus). Similar to the bovine endometrium, ovine FOXL2 endometrial expression was low during the luteal phase of the oestrous cycle (4 to 12 days post-oestrus) and at implantation (15 days post-oestrus) while mRNA and protein expression significantly increased during the luteolytic phase (day 15 post-oestrus 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 FOXL2 expression in caruncles compared with the control group (1.4-fold, p < 0.05). Ovariectomized ewes or cows that were supplemented with exogenous progesterone for 12 days or 6 days, respectively, had lower endometrial FOXL2 expression compared with control ovariectomized females (sheep, mRNA, 1.8-fold; protein, 2.4-fold; cattle; mRNA, 2.2-fold; p < 0.05). Exogenous oestradiol treatments for 12 days in sheep or 2 days in cattle did not affect FOXL2 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 FOXL2 expression. Using in vitro assays with COS7 cells we also demonstrated that progesterone regulates the FOXL2 promoter activity through the progesterone receptor. Collectively, our findings imply that endometrial FOXL2 is, as a direct target of progesterone, involved in early pregnancy and implantation.

The Influence of Intravaginal Gestagens Treatment on the Morphological Features and Endometrial Steroid Hormone Receptors Content during Anestrus Type II in Dairy Cattle

“…In addition, P4 acts on target cells through membrane receptors which exist in two main isoforms: A and B. PR B is a progesterone-dependent gene activator, while PR A is a potent inhibitor of PR B that reduces the effects of P4 in tissue [30]. Thus, higher tissue expression of PR increases the sensitivity of the endometrium, and can stimulate the proliferation of endometrial cells [31]. Therefore, the concomitant increase in tissue AB PR expression and the endometrial response to hormonal stimulation may ensure high pregnancy rates in the first insemination following treatment.…”

Understanding conceptus–maternal interactions: what tools do we need to develop?

“…Bovine embryos don't depend on exposure to the maternal system until after blastocyst hatching, as evidenced by in vitro embryo culture and successful pregnancy after transfer at this point. In cattle, the blastocyst hatches from the zona pellucida around day 9, where the conceptus undergoes a period of rapid elongation into a filamentous conceptus (Spencer 2013), which begins implantation on day 16-20 after ovulation (Eozenou et al 2020). This differs in humans, where the implantation processes of apposition occur immediately posthatching (Kim and Kim 2017).…”

Early Gonadal Development and Sex Determination in Mammal

“…The FOXL2 becomes involved in follicle development by inducing Follicle-stimulating hormone (FSH) synthesis following sex determination [ 118 , 119 ], whose expression is regulated by ovarian hormones [ 120 , 121 ]. Furthermore, FOXL2 plays a role in the development and maintenance of the ovary via interacting with STAR [ 122 ], ESR2 [ 123 ]), and p27 [ 124 ].…”