GGPP-Mediated Protein Geranylgeranylation in Oocyte Is Essential for the Establishment of Oocyte-Granulosa Cell Communication and Primary-Secondary Follicle Transition in Mouse Ovary.
GGPP-Mediated Protein Geranylgeranylation in Oocyte Is Essential for the Establishment of Oocyte-Granulosa Cell Communication and Primary-Secondary Follicle Transition in Mouse Ovary.
复制标题
卵母细胞中 GGPP 介导的蛋白质香叶基香叶基化对于小鼠卵巢中卵母细胞-颗粒细胞通讯和初级-次级卵泡转变的建立至关重要
DOI：
10.1371/journal.pgen.1006535
复制
发表时间：
2017-01
期刊：
影响因子：
4.5
通讯作者：
Li CJ
中科院分区：
文献类型：
--
作者：
Jiang C;Diao F;Sang YJ;Xu N;Zhu RL;Wang XX;Chen Z;Tao WW;Yao B;Sun HX;Huang XX;Xue B;Li CJ
卵泡发生是一个渐进的、高度调节的过程，是为以后的生殖生活提供卵子所必需的，需要卵母细胞和颗粒细胞之间的双向通讯。这种物理连接介导的通信不仅将信号从卵母细胞传递到颗粒细胞，调节其增殖，而且还将代谢物从颗粒细胞传递到卵母细胞进行生物合成。然而，建立这种通信的基本机制在很大程度上是未知的。在这里，我们报告，卵母细胞牛儿基牛儿基二磷酸（GGPP），参与蛋白牛儿基牛儿基化的代谢中间体，需要建立卵母细胞颗粒细胞通信。卵母细胞中GGPP和香叶基香叶基二磷酸合酶（Ggpps）水平在卵泡发育早期增加。选择性去除小鼠卵母细胞中的GGPP会损害颗粒细胞的增殖、初级卵泡向次级卵泡的转化和雌性生育力。从机制上讲，GGPP耗竭抑制Rho GT3香叶基香叶基化及其GT3活性，这是导致卵母细胞细胞质中细胞连接蛋白积累以及卵母细胞和颗粒细胞之间未能维持物理连接的原因。GGPP消融还阻断Rab 27 a香叶基香叶基化，这可能是导致卵母细胞物质（如Gdf 9）分泌受损的原因。此外，GGPP给药恢复了Ggpps耗竭小鼠的卵母细胞-颗粒细胞接触、颗粒细胞增殖和初级-次级卵泡转换的缺陷。我们的研究提供的证据表明，GCPP介导的蛋白香叶基香叶基化有助于卵母细胞-颗粒细胞通讯的建立，然后调节初级-次级卵泡转换，这是女性生殖功能所必需的卵泡发生的关键阶段。
Folliculogenesis is a progressive and highly regulated process, which is essential to provide ova for later reproductive life, requires the bidirectional communication between the oocyte and granulosa cells. This physical connection-mediated communication conveys not only the signals from the oocyte to granulosa cells that regulate their proliferation but also metabolites from the granulosa cells to the oocyte for biosynthesis. However, the underlying mechanism of establishing this communication is largely unknown. Here, we report that oocyte geranylgeranyl diphosphate (GGPP), a metabolic intermediate involved in protein geranylgeranylation, is required to establish the oocyte-granulosa cell communication. GGPP and geranylgeranyl diphosphate synthase (Ggpps) levels in oocytes increased during early follicular development. The selective depletion of GGPP in mouse oocytes impaired the proliferation of granulosa cells, primary-secondary follicle transition and female fertility. Mechanistically, GGPP depletion inhibited Rho GTPase geranylgeranylation and its GTPase activity, which was responsible for the accumulation of cell junction proteins in the oocyte cytoplasm and the failure to maintain physical connection between oocyte and granulosa cells. GGPP ablation also blocked Rab27a geranylgeranylation, which might account for the impaired secretion of oocyte materials such as Gdf9. Moreover, GGPP administration restored the defects in oocyte-granulosa cell contact, granulosa cell proliferation and primary-secondary follicle transition in Ggpps depletion mice. Our study provides the evidence that GGPP-mediated protein geranylgeranylation contributes to the establishment of oocyte-granulosa cell communication and then regulates the primary-secondary follicle transition, a key phase of folliculogenesis essential for female reproductive function.