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FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

Caroline Eozenou, Audrey Lesage-Padilla, Vincent Mauffré, Gareth Healey Orcid Logo, Sylvaine Camous, Philippe Bolifraud, Corinne Giraud-Delville, Daniel Vaiman, Takashi Shimizu, Akio Miyamoto, Martin Sheldon Orcid Logo, Fabienne Constant, Maëlle Pannetier, Olivier Sandra

International Journal of Molecular Sciences, Volume: 21, Issue: 4, Start page: 1478

Swansea University Authors: Gareth Healey Orcid Logo, Martin Sheldon Orcid Logo

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DOI (Published version): 10.3390/ijms21041478

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 pre...

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Published in: International Journal of Molecular Sciences
ISSN: 1422-0067
Published: MDPI AG 2020
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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 &lt; 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 &lt; 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. 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spelling 2020-10-23T11:30:44.8623906 v2 53643 2020-02-27 FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants 5926519f89187489cfd5e1478aa188b1 0000-0001-9531-1220 Gareth Healey Gareth Healey true false ab0f74b794e59cc270c69e63ee1d9748 0000-0001-7902-5558 Martin Sheldon Martin Sheldon true false 2020-02-27 PMSC 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. Journal Article International Journal of Molecular Sciences 21 4 1478 MDPI AG 1422-0067 FOXL2; endometrium; sheep; cattle; progesterone 21 2 2020 2020-02-21 10.3390/ijms21041478 COLLEGE NANME Medicine COLLEGE CODE PMSC Swansea University 2020-10-23T11:30:44.8623906 2020-02-27T09:27:39.2919258 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Caroline Eozenou 1 Audrey Lesage-Padilla 2 Vincent Mauffré 3 Gareth Healey 0000-0001-9531-1220 4 Sylvaine Camous 5 Philippe Bolifraud 6 Corinne Giraud-Delville 7 Daniel Vaiman 8 Takashi Shimizu 9 Akio Miyamoto 10 Martin Sheldon 0000-0001-7902-5558 11 Fabienne Constant 12 Maëlle Pannetier 13 Olivier Sandra 14 53643__16717__f61c3164f4954e289003e6944e2dc694.pdf ijms-21-01478-v2.pdf 2020-02-28T13:45:32.6410341 Output 2757985 application/pdf Version of Record true Released under the terms of a Creative Commons Attribution License (CC-BY). true eng http://creativecommons.org/licenses/by/4.0/
title FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants
spellingShingle FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants
Gareth Healey
Martin Sheldon
title_short FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants
title_full FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants
title_fullStr FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants
title_full_unstemmed FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants
title_sort FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants
author_id_str_mv 5926519f89187489cfd5e1478aa188b1
ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv 5926519f89187489cfd5e1478aa188b1_***_Gareth Healey
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author Gareth Healey
Martin Sheldon
author2 Caroline Eozenou
Audrey Lesage-Padilla
Vincent Mauffré
Gareth Healey
Sylvaine Camous
Philippe Bolifraud
Corinne Giraud-Delville
Daniel Vaiman
Takashi Shimizu
Akio Miyamoto
Martin Sheldon
Fabienne Constant
Maëlle Pannetier
Olivier Sandra
format Journal article
container_title International Journal of Molecular Sciences
container_volume 21
container_issue 4
container_start_page 1478
publishDate 2020
institution Swansea University
issn 1422-0067
doi_str_mv 10.3390/ijms21041478
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.
published_date 2020-02-21T04:06:42Z
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score 11.036116

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