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R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth

R-spondin2 (RSPO2) is a member of the R-spondin family, which are secreted activators of the WNT/β-catenin (CTNNB1) signaling pathway. In the mouse postnatal ovary, WNT/CTNNB1 signaling is active in the oocyte and in the neighboring supporting cells, the granulosa cells. Although the role of Rspo2 h...

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Autores principales: De Cian, Marie-Cécile, Gregoire, Elodie P., Le Rolle, Morgane, Lachambre, Simon, Mondin, Magali, Bell, Sheila, Guigon, Céline J., Chassot, Anne-Amandine, Chaboissier, Marie-Christine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493947/
https://www.ncbi.nlm.nih.gov/pubmed/32341451
http://dx.doi.org/10.1038/s41418-020-0547-7
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author De Cian, Marie-Cécile
Gregoire, Elodie P.
Le Rolle, Morgane
Lachambre, Simon
Mondin, Magali
Bell, Sheila
Guigon, Céline J.
Chassot, Anne-Amandine
Chaboissier, Marie-Christine
author_facet De Cian, Marie-Cécile
Gregoire, Elodie P.
Le Rolle, Morgane
Lachambre, Simon
Mondin, Magali
Bell, Sheila
Guigon, Céline J.
Chassot, Anne-Amandine
Chaboissier, Marie-Christine
author_sort De Cian, Marie-Cécile
collection PubMed
description R-spondin2 (RSPO2) is a member of the R-spondin family, which are secreted activators of the WNT/β-catenin (CTNNB1) signaling pathway. In the mouse postnatal ovary, WNT/CTNNB1 signaling is active in the oocyte and in the neighboring supporting cells, the granulosa cells. Although the role of Rspo2 has been previously studied using in vitro experiments, the results are conflicting and the in vivo ovarian function of Rspo2 remains unclear. In the present study, we found that RSPO2/Rspo2 expression is restricted to the oocyte of developing follicles in both human and mouse ovaries from the beginning of the follicular growth. In mice, genetic deletion of Rspo2 does not impair oocyte growth, but instead prevents cell cycle progression of neighboring granulosa cells, thus resulting in an arrest of follicular growth. We further show this cell cycle arrest to be independent of growth promoting GDF9 signaling, but rather associated with a downregulation of WNT/CTNNB1 signaling in granulosa cells. To confirm the contribution of WNT/CTNNB1 signaling in granulosa cell proliferation, we induced cell type specific deletion of Ctnnb1 postnatally. Strikingly, follicles lacking Ctnnb1 failed to develop beyond the primary stage. These results show that RSPO2 acts in a paracrine manner to sustain granulosa cell proliferation in early developing follicles. Taken together, our data demonstrate that the activation of WNT/CTNNB1 signaling by RSPO2 is essential for oocyte-granulosa cell interactions that drive maturation of the ovarian follicles and eventually female fertility.
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spelling pubmed-74939472020-10-01 R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth De Cian, Marie-Cécile Gregoire, Elodie P. Le Rolle, Morgane Lachambre, Simon Mondin, Magali Bell, Sheila Guigon, Céline J. Chassot, Anne-Amandine Chaboissier, Marie-Christine Cell Death Differ Article R-spondin2 (RSPO2) is a member of the R-spondin family, which are secreted activators of the WNT/β-catenin (CTNNB1) signaling pathway. In the mouse postnatal ovary, WNT/CTNNB1 signaling is active in the oocyte and in the neighboring supporting cells, the granulosa cells. Although the role of Rspo2 has been previously studied using in vitro experiments, the results are conflicting and the in vivo ovarian function of Rspo2 remains unclear. In the present study, we found that RSPO2/Rspo2 expression is restricted to the oocyte of developing follicles in both human and mouse ovaries from the beginning of the follicular growth. In mice, genetic deletion of Rspo2 does not impair oocyte growth, but instead prevents cell cycle progression of neighboring granulosa cells, thus resulting in an arrest of follicular growth. We further show this cell cycle arrest to be independent of growth promoting GDF9 signaling, but rather associated with a downregulation of WNT/CTNNB1 signaling in granulosa cells. To confirm the contribution of WNT/CTNNB1 signaling in granulosa cell proliferation, we induced cell type specific deletion of Ctnnb1 postnatally. Strikingly, follicles lacking Ctnnb1 failed to develop beyond the primary stage. These results show that RSPO2 acts in a paracrine manner to sustain granulosa cell proliferation in early developing follicles. Taken together, our data demonstrate that the activation of WNT/CTNNB1 signaling by RSPO2 is essential for oocyte-granulosa cell interactions that drive maturation of the ovarian follicles and eventually female fertility. Nature Publishing Group UK 2020-04-27 2020-10 /pmc/articles/PMC7493947/ /pubmed/32341451 http://dx.doi.org/10.1038/s41418-020-0547-7 Text en © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
De Cian, Marie-Cécile
Gregoire, Elodie P.
Le Rolle, Morgane
Lachambre, Simon
Mondin, Magali
Bell, Sheila
Guigon, Céline J.
Chassot, Anne-Amandine
Chaboissier, Marie-Christine
R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
title R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
title_full R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
title_fullStr R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
title_full_unstemmed R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
title_short R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
title_sort r-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493947/
https://www.ncbi.nlm.nih.gov/pubmed/32341451
http://dx.doi.org/10.1038/s41418-020-0547-7
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