Guo Jing, Shi Lanying, Gong Xuhong, Jiang Mengjie, Yin Yaoxue, Zhang Xiaoyun, Yin Hong, Li Hui, Emori Chihiro, Sugiura Koji, Eppig John J, Su You-Qiang
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
J Cell Sci. 2016 Aug 15;129(16):3091-103. doi: 10.1242/jcs.182642. Epub 2016 Jun 29.
Communication between oocytes and their companion somatic cells promotes the healthy development of ovarian follicles, which is crucial for producing oocytes that can be fertilized and are competent to support embryogenesis. However, how oocyte-derived signaling regulates these essential processes remains largely undefined. Here, we demonstrate that oocyte-derived paracrine factors, particularly GDF9 and GDF9-BMP15 heterodimer, promote the development and survival of cumulus-cell-oocyte complexes (COCs), partly by suppressing the expression of Ddit4l, a negative regulator of MTOR, and enabling the activation of MTOR signaling in cumulus cells. Cumulus cells expressed less Ddit4l mRNA and protein than mural granulosa cells, which is in striking contrast to the expression of phosphorylated RPS6 (a major downstream effector of MTOR). Knockdown of Ddit4l activated MTOR signaling in cumulus cells, whereas inhibition of MTOR in COCs compromised oocyte developmental competence and cumulus cell survival, with the latter likely to be attributable to specific changes in a subset of transcripts in the transcriptome of COCs. Therefore, oocyte suppression of Ddit4l expression allows for MTOR activation in cumulus cells, and this oocyte-dependent activation of MTOR signaling in cumulus cells controls the development and survival of COCs.
卵母细胞与其相伴的体细胞之间的通讯促进卵巢卵泡的健康发育，这对于产生能够受精并支持胚胎发生的卵母细胞至关重要。然而，卵母细胞衍生的信号如何调节这些重要过程在很大程度上仍不清楚。在此，我们证明卵母细胞衍生的旁分泌因子，特别是生长分化因子9（GDF9）和GDF9 - 骨形态发生蛋白15（BMP15）异二聚体，部分通过抑制雷帕霉素靶蛋白（MTOR）的负调节因子Ddit4l的表达并使卵丘细胞中的MTOR信号通路激活，从而促进卵丘细胞 - 卵母细胞复合体（COC）的发育和存活。卵丘细胞中Ddit4l的mRNA和蛋白质表达低于颗粒膜细胞，这与磷酸化核糖体蛋白S6（MTOR的主要下游效应物）的表达形成鲜明对比。敲低Ddit4l可激活卵丘细胞中的MTOR信号通路，而抑制COC中的MTOR会损害卵母细胞的发育能力和卵丘细胞的存活，后者可能归因于COC转录组中一部分转录本的特定变化。因此，卵母细胞对Ddit4l表达的抑制使得卵丘细胞中的MTOR被激活，并且卵丘细胞中这种依赖于卵母细胞的MTOR信号通路激活控制着COC的发育和存活。
