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.
Highlights
In mammals, successful implantation and pregnancy depends on a tightly regulated cross-talk between the ovary, the endometrium and the conceptus, which takes place during the peri-implantation period [1,2,3,4]
Studies have identified direct target genes of ESR and Progesterone Receptor (PGR) in humans, rodents and cattle [39]. These genes are involved in the repression of the E2 signalling pathway (NR2F2/COUP-TFII; [38]), proliferation of endometrial cells (i.e., IGF1 and EGR1; [35,38]), uterine receptivity (FOXO1, [40]) and decidualisation (NR2F2/COUP-TFII, WNT4, HOXA10; [38])
Using transiently transfected COS-7 cells, Forkhead Box L2 (FOXL2) promoter activity was increased by P4 treatment when PGR-A, PGR-B or a combination of both PGR were overexpressed. (Figure 5, p < 0.01; p < 0,001)
Summary
Successful implantation and pregnancy depends on a tightly regulated cross-talk between the ovary, the endometrium and the conceptus (embryonic disk and extra-embryonic tissues), which takes place during the peri-implantation period [1,2,3,4]. Studies have identified direct target genes of ESR and PGR in humans, rodents and cattle [39] These genes are involved in the repression of the E2 signalling pathway (NR2F2/COUP-TFII; [38]), proliferation of endometrial cells (i.e., IGF1 and EGR1; [35,38]), uterine receptivity (FOXO1, [40]) and decidualisation (NR2F2/COUP-TFII, WNT4, HOXA10; [38]). This non-exhaustive list of steroids targeting genes in the endometrium includes transcription factors that represent regulation nodes of endometrial receptivity and physiology. The biological actions of E2 and P4 are essential for pregnancy outcome but their orchestration is not yet fully elucidated
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