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RSPO2, an essential protein for ovarian function and fertility

The proteins of the R-spondin family are secreted proteins which regulate the activation of the WNT/β-catenin signaling pathway (CTNNB1), a central pathway in ovarian development. The expression of Rspo2, recently described in the oocyte at the time of birth, suggests that this gene plays an important role in follicular growth and is drawing the attention of many teams working on ovarian failure. In their latest in vivo study conducted on mice, the team of Marie-Christine Chaboissier, CNRS Research Director at the Valrose Institute of Biology, confirmed the important role of the RSPO2 protein in oocyte-granulosa cell interactions via the WNT/CTNNB1 signaling pathway. Their study shows that the RSPO2 protein regulates the maturation of ovarian follicles and, consequently, female fertility. Their research was published online at the end of April in the Cell Death and Differentiation journal.

Publication : 15/05/2020
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In the ovary, cellular communication between the oocyte and neighboring somatic cells, or granulosa cells, is essential for the follicular growth that ultimately leads to the release of the oocyte during ovulation. In mice, when follicular growth begins at birth, the ovigerous cords break down into individual germ cells which surround themselves with a layer of elongated granulosa cells and form a primordial follicle. Once formed, most of the primordial follicles enter a resting phase until they are activated during the cyclic process of ovulation.

The activated primordial follicles then grow rapidly as the oocyte volume increases and the granulosa cells proliferate, first taking on the shape of a cube, and then of a column. These changes in shape caused by the growing proliferation of granulosa cells are critical for further follicular development because they increase intercellular contact between adjacent granulosa cells and their adhesion to the surface of the oocytes. Follicular growth continues with the formation of a second inner layer of granulosa cells leading to the development of secondary follicles. The granulosa cells then divide to form tertiary, antral and pre-ovulatory follicles with a granulosa composed of more than 50,000 cells.

Previous studies conducted in vitro have shown that R-spondine2 (RSPO2) could play a role in follicle maturation. However, the results were contradictory and the in vivo ovarian function of the REPO2 gene remained uncertain. In this study, the researchers demonstrated in vivo that RSPO2/Rspo2 expression is restricted to the oocyte of developing follicles in both humans and mice. They showed that in mice, inactivation of the gene coding for protein RSPO2 does not alter the growth of oocytes, but rather prevents cell cycle progression of the neighboring granulosa cells, resulting in an arrest of follicular growth. The team also showed that this cell cycle arrest is independent of the GDF9 signaling pathway, the factor recognized to promote this growth, but is rather associated with a downregulation of the WNT/CTNNB1 signaling pathway in granulosa cells. To confirm the role of this signaling pathway in follicular growth, the researchers used a conditional deletion model of Ctnnb1 (β-catenin) in granulosa cells. The follicles lacking CTNNB1 did not develop beyond the primary stage. These results show that RSPO2 acts in a paracrine manner to activate granulosa cell proliferation in the follicles during early development.

This study demonstrates that the activation of the WNT/CTNNB1 signaling by the RSPO2 protein is essential for interactions between the oocyte and the granulosa cells and determines the maturation of the ovarian follicles, and therefore female fertility.

Title: R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth.
Authors: Marie-Cécile De Cian, Elodie P. Gregoire, Morgane Le Rolle, Simon Lachambre, Magali Mondin, Sheila Bell, Céline J. Guigon, Anne Amandine Chassot and Marie-Christine Chaboissier
Valrose Institute of Biology (iBV) - Université Côte d'Azur, CNRS, Inserm
Cincinnati Children's Hospital Medical Center, Ohio, USA
Université de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, France
iBV - Université Côte d'Azur, CNRS, Inserm & University of Bordeaux, UMS 3420 CNRS, Inserm

Contacts: Marie-Christine Chaboissier, CNRS Research Director
Sex determination in mice - LABEX SIGNALIFE team
Valrose Institute of Biology (iBV) - 0489150725

Proposed model for RSPO2 signaling in the ovaries. (©Springer Nature publications)
(A) Follicular growth requires the presence of the RSPO2 protein secreted by oocytes. RSPO2 promotes the stabilization of the protein CTNNB1 (-catenine) in the neighboring granulosa cells, and, in turn, the proliferation and adhesion of these cells. This leads to follicular growth and the development of antral follicles.
(B) When the gene coding for the RSPO2 protein is not expressed, the activation of the protein CTNNB1 is decreased in granulosa cells, thus leading to defects in cell proliferation and adhesion.
Photo credit Flower photo created by freepic.diller -