R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth
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DOI：
10.1038/s41418-020-0547-7
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发表时间：
2020-04-27
影响因子：
12.4
通讯作者：
Chaboissier, Marie-Christine
中科院分区：
文献类型：
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作者：
De Cian, Marie-Cecile;Gregoire, Elodie P.;Chaboissier, Marie-Christine
R-spondin2 (RSPO2) 是 R-spondin 家族的成员，是 WNT/β-连环蛋白 (CTNNB1) 信号通路的分泌激活剂。在小鼠出生后卵巢中，WNT/CTNNB1 信号在卵母细胞和邻近的支持细胞（颗粒细胞）中活跃。尽管之前已经通过体外实验研究了Rspo2的作用，但结果是相互矛盾的，并且Rspo2的体内卵巢功能仍不清楚。在本研究中，我们发现从卵泡生长开始，RSPO2/Rspo2 表达仅限于人类和小鼠卵巢中发育卵泡的卵母细胞。在小鼠中，Rspo2 的基因缺失不会损害卵母细胞的生长，而是会阻止邻近颗粒细胞的细胞周期进程，从而导致卵泡生长停滞。我们进一步表明，这种细胞周期停滞与促进生长的 GDF9 信号传导无关，而是与颗粒细胞中 WNT/CTNNB1 信号传导的下调相关。为了证实 WNT/CTNNB1 信号传导在颗粒细胞增殖中的作用，我们在出生后诱导细胞类型特异性缺失 Ctnnb1。引人注目的是，缺乏 Ctnnb1 的卵泡无法发育超过初级阶段。这些结果表明，RSPO2 以旁分泌方式发挥作用，维持早期发育卵泡中的颗粒细胞增殖。综上所述，我们的数据表明，RSPO2 激活 WNT/CTNNB1 信号对于卵母细胞-颗粒细胞相互作用至关重要，从而驱动卵泡成熟并最终促进女性生育能力。
R-spondin2 (RSPO2) is a member of the R-spondin family, which are secreted activators of the WNT/beta-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.