Uterine Foxl2 regulates the adherence of the Trophectoderm cells to the endometrial epithelium

Elbaz, Meyer; Hadas, Ron; Bilezikjian, Louise M.; Gershon, Eran

doi:10.1186/s12958-018-0329-y

Cited by 15 publications

(9 citation statements)

References 38 publications

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“…In mammalian species, new reproductive tissues appeared, including the uterus, placenta and mammary gland. Collectively, our data as well as GEO profiles, NextProt-Beta data and the human protein atlas have documented the expression of FOXL2 in every female reproductive tissue: the oviduct, uterus (endometrium and myometrium), mammary gland and placenta [52,[54][55][56]63,73,88]. Interestingly, whereas FOXL2 is expressed in each reproductive tissue of mammalian female, its regulation varies with the nature of the reproductive tissue.…”

Section: Discussionmentioning

confidence: 58%

“…However, FOXL2 is also expressed in the bovine endometrium and its expression was regulated throughout the oestrous cycle and early pregnancy [52]. Endometrial expression of FOXL2 has been confirmed in several mammals, including mice [55,56], humans [54] and camels [63]. Surprisingly, IFNT, the signal for maternal recognition of pregnancy in ruminants, was not involved in FOXL2 gene regulation [52].…”

Section: Discussionmentioning

confidence: 99%

“…At the time of implantation, transcriptional regulation of transcription factor expression was reported for several members of the winged-helix/forkhead domain (FOX) transcription factors family in the bovine endometrium [44], including Forkhead Box L2 (FOXL2), which appears to be important in the endometrium as well as a key gene involved in ovarian differentiation and maintenance of ovarian function from foetal life to adulthood [51][52][53]. Since our first identification of FOXL2 in the endometrium [52], this transcription factor has been reported to be expressed in endometriotic lesions in humans [54], involved in uterus maturation [55] as well as endometrial cell adhesion with the trophectoderm in mice [56]. However, regulation of FOXL2 gene expression was IFNT-independent [52] and there was a negative correlation between circulating P4 concentrations and FOXL2 gene expression in the bovine endometrium [52].…”

Section: Introductionmentioning

confidence: 99%

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FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

Eozénou

Lesage-Padilla

Mauffré

et al. 2020

IJMS

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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.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

Eozénou

Lesage-Padilla

Mauffré

et al. 2020

IJMS

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“…Blastocyst attachment assay was performed as described previously 19,20 . Briefly, blastocysts were infected with lentiviruses for five hours, washed and immediately labeled with Vybrant Cell-Labeling Solution (ThermoFisher Scientific, Waltham, MS) for 20 minutes, before transferring unselectively to confluent Ishikawa cell monolayers in a 96-well plate coated with Matrigel (Invitro technologies, Victoria, Australia).…”

Section: Methodsmentioning

confidence: 99%

Production of Hyaluronan by the Trophectoderm is a Prerequisite for Mouse Blastocyst Attachment

Hadas

Gershon²,

Cohen

et al. 2020

Preprint

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13by blastocyst attachment to the endometrial epithelium. Hyaluronan is a major ECM component known to regulate 14 adhesion-associated biological processes in various physiological settings. We hypothesized that hyaluronan may 15 facilitate blastocyst attachment. In order to test our hypothesis, we characterized the blastocyst expression of 16 hyaluronan synthesizing and degrading enzymes, as well as the expression of hyaluronan receptors during 17 attachment. The functional impact of hyaluronan was challenged by the use of mouse transgenic blastocysts, in 18 which genes encoding for hyaluronan synthesizing enzymes were deleted using lentiviral incorporation of Cas-9 19 endonuclease alongside specific short-guide RNAs into the embryonic trophectoderm. Embryos with transgenic 20 trophectoderm were tested for their attachment in vitro, or assessed for implantation in vivo, upon transfer to 21 foster dams. Deletion of the trophectoderm hyaluronan biosynthesis significantly reduced the number of 22 blastocysts attached to human uterine epithelium cells in vitro. Reduced attachment was also observed in vivo, in 23 pregnant mice carrying blastocysts with hyaluronan-depleted trophectoderm. In agreement, trophectoderm 24 expression of osteopontin, was downregulated upon depletion of hyaluronan. MRI measurements revealed a 25 decrease in uterine blood vessels permeability. Uterine expression of VEGF-A, PTGS-2 and uterine osteopontin, 26 which constitute the immediate response to blastocyst attachment was also reduced. Furthermore, impaired 27 implantation, associated with a decrease in hyaluronan synthesis in the mural trophectoderm, obtained upon 28 tamoxifen treatment, has been recovered by LIF administration. These results demonstrate that estrogen-regulated 29 hyaluronan-synthesis in the trophectoderm is indispensable for mouse blastocysts attachment to the uterine 30 epithelium. 31 32 33Implantation, during which the embryo attaches to and invades the maternal endometrium 1 is essential for 34 successful pregnancy. In humans, natural conception per cycle is poor (~30%), and implantation defects were 35 implicated in 75% of failed pregnancies 2,3 . Implantation is initiated by blastocyst apposition, which in mice, takes 36 place on the fourth day of pregnancy (E4.0), followed by the attachment of embryonic mural trophectoderm cells 37 to the uterine luminal epithelium, and the subsequent invasion of the uterine epithelium into the implantation 38 crypt toward the anti-mesometrial pole 4 . These physiological events require both, a receptive uterus as well as a 39 high quality blastocyst 5 . Ovarian-secreted estrogen directly regulates blastocyst activation, in a temporally 40 synchronized manner, preventing its dormancy 6 . The activated blastocyst attaches to the uterine epithelium, 41 stimulating in response, a local up-regulation of the pro-angiogenic factor, VEGF-A. A resulting increased 42 endometrial vascular permeability in the implantation chamber has been monitored in vivo by dynamic contrast-43 enha...

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“…We call a gene the target of a SNP if (1) the SNP is located in the promoter (< 1 kb of TSS) of that gene; or (2) the promoter of that gene has a pcHi-C interaction with a region within 1 kb of the SNP. In the case of rs147843771 at the FOXL2 locus, the target was defined by literature evidence 44 . The number of credible SNPs at each region are shown in Figure 7B.…”

Section: Integrated Analysis Of Gwas and Decidual Cell Functional Annmentioning

confidence: 99%

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

Sakabe

Aneas

Knoblauch

et al. 2020

Preprint

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While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary deciduaderived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancyrelevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

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Uterine Foxl2 regulates the adherence of the Trophectoderm cells to the endometrial epithelium

Cited by 15 publications

References 38 publications

FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

Production of Hyaluronan by the Trophectoderm is a Prerequisite for Mouse Blastocyst Attachment

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

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