Abstract
BackgroundForkhead Transcription Factor L2 (FOXL2) is a member of the forkhead family with important roles in reproduction. Recent studies showed that FOXL2 is expressed in human and bovine endometrium and that its levels fluctuate during pregnancy. In this study, we aimed at evaluating the expression and function of FOXL2 in embryo implantation.MethodsMouse uteri at different days of pregnancy were isolated and analyzed for the expression and localization of FOXL2. A lentiviral strategy was further employed to either knockdown or overexpress FOXL2 in non-receptive human endometrial AN3-CA cells and in receptive Ishikawa cells, respectively. These genetically modified cells were compared to cells infected with a control lentivirus to determine the function of FOXL2 in trophectoderm cells adherence to Endometrial Epithelium was associated with the expression of genes known to be involved in acquisition of uterine receptivity.ResultsWe report that FOXL2 is expressed in both, the luminal epithelium and the myometrium of the mouse uterus and that its expression declines prior to implantation. We found that endometrial cells expressing low FOXL2 levels, either endogenous or genetically manipulated, were associated with a higher attachment rate of mouse blastocysts or human Jeg3 spheroids and mouse blastocysts. In accordance, low-FOXL2 levels were associated with changes in the expression level of components of the Wnt/Fzd and apoptotic pathways, both of which are involved in uterine receptivity. Furthermore, FOXL2 expression was inversely correlated with G-protein signaling protein 2 (Rgs2) and cytokine expression.ConclusionsThese results suggest that FOXL2 interferes with embryo attachment. Better understanding of the function of FOXL2 in the uterus would possibly suggest novel strategies for treatment of infertility attributed to repeated implantation failure.
Highlights
Forkhead Transcription Factor L2 (FOXL2) is a member of the forkhead family with important roles in reproduction
We found that the FOXL2 protein, which is high upon establishment of pregnancy, significantly decreases prior to implantation
This study reported that Foxl2 overexpression activated the transcription of several anti-apoptotic genes, such as immediate-early response 3 (Ier3), BCL2related protein A1 (Bcl2A1) and tumor necrosis factor alpha-induced protein 3 (Tnfaip3) [3], and increased transcription of pro-apoptotic factors, including activating transcription factor 3 (Atf3) [3]
Summary
Forkhead Transcription Factor L2 (FOXL2) is a member of the forkhead family with important roles in reproduction. Later studies suggest that Foxl regulates granulosa cell proliferation [5] and ovarian G-protein signaling protein 2 (RGS2) [3, 6]. These multi-functional GTPase-accelerating proteins inactivate the alphasubunit of G proteins and rapidly switch off the G protein-coupled receptor signaling pathways by promoting GTP hydrolysis [7, 8]. Another recent study found that FOXL2 directly modulates estrogen receptor beta (ESR2) expression through a newly identified intronic element [4]. FOXL2 in the murine pregnant uterus, is exclusively expressed in the implantation sites [7]
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