FOXL2 is a new progesterone-regulated gene in the endometrium

Abstract : In mammals, mutual actions of estrogens and progesterone on their uterine receptors are essential for endometrium receptivity and conceptus implantation. In cattle we showed that FOXL2 -a key gene for ovarian differentiation and maintenance- is expressed and regulated in endometrium during oestrous cycle, a finding confirmed in murine and human endometrium. The present study aims to determine if FOXL2 is a progesterone-target gene in the bovine endometrium. Using various experimenta models in cattle, our results indicated (i) a negative correlation between FOXL2 gene expression and progesterone (P4) blood levels (ii) a significant reduction of FOXL2 transcript level in ovariectomized cows supplemented with P4 for 6 days (2.2-fold vs. control ovariectomized cows, P < 0.05) (iii) a significant decrease in FOXL2 mRNA level in bovine endometrial explants incubated with P4 (10-5 M) for 48h (2.4-fold vs. control explants, P < 0.05). No impact of oestradiol on FOXL2 gene expression was detected in these conditions. In order to confirm the regulation of FOXL2 promoter by P4, COS7 cells were transfected with a caprine FOXL2 reporter gene and progesterone receptor (PR) A or B expression vectors. In the presence of PRA and PRB, P4 (10-7 M) stimulated the activity of FOXL2 promoter (2.8-fold). Mutation of the P4 Response Element (PRE) in the caprine FOXL2 promoter abrogated the activity of this promoter in P4-treated COS7 cells overexpressing PRA/PRB. Collectively, our data show that reduced FOXL2 expression in the endometrium during the luteal phase results from the down-regulation of PRA/B known to occur in the presence of P4. Determining the biological actions of FOXL2 will be mandatory to define the contribution of this transcription factor in the regulation of sensor and driver properties of the endometrium.