Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice.
Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice.
复制标题
MTOR 卵母细胞阶段特异性影响决定小鼠颗粒细胞命运和卵母细胞质量
DOI：
10.1073/pnas.1800352115
复制
发表时间：
2018-06-05
影响因子：
11.1
通讯作者：
Su YQ
中科院分区：
文献类型：
--
作者：
Guo J;Zhang T;Guo Y;Sun T;Li H;Zhang X;Yin H;Cao G;Yin Y;Wang H;Shi L;Guo X;Sha J;Eppig JJ;Su YQ
意义MTOR（mechanistic target of rapamycin）是细胞代谢、增殖和分化重要途径的整合者，在卵母细胞发育的所有阶段都有表达。原始卵母细胞是一种非增殖性、非生长性的潜在卵子储备，在哺乳动物雌性的整个生殖寿命中得以维持。使用条件性基因敲除，我们确定了MTOR在原始卵母细胞和生长卵母细胞中的作用。原始卵母细胞中的MTOR依赖性途径不需要维持原始卵母细胞池的活力或将其招募到生长的卵母细胞群中，但对于维持卵母细胞基因组完整性、维持卵巢卵泡发育和生育力是必不可少的。在卵母细胞的生长过程中，MTOR依赖性途径是促进减数分裂完成和胚胎发育所必需的。MTOR（mechanistic target of rapamycin，雷帕霉素的机械靶点）是广泛公认的细胞代谢、增殖和分化的关键信号和途径的整合剂。在这里，我们表明，条件性敲除（cKO）的MTOR在原始或生长中的卵母细胞引起不育，但差异影响卵母细胞的质量，颗粒细胞的命运，和卵泡发育。在非生长的原始卵母细胞中，Mtor的cKO引起卵泡发育缺陷，导致卵母细胞的进行性变性和颗粒细胞身份的丧失，与获得未成熟的支持细胞样特征一致。虽然Mtor在原始卵母细胞阶段被删除，DNA损伤在卵母细胞中积累在其后期的生长过程中，并有一个显着的改变，在少数卵母细胞的转录组，实现了完全生长的阶段。尽管在卵母细胞开始生长后删除Mtor也会影响卵母细胞的质量和生育能力，但这些都不会明显影响卵泡发生或卵母细胞转录组。然而，成熟卵母细胞中的蛋白质组发生了显著变化。特别是，PRC1（胞质分裂蛋白调节因子1）的下调损害了第一次减数分裂的完成。因此，MTOR依赖的途径在原始或生长的卵母细胞差异影响下游过程，包括卵泡发育，早期颗粒细胞的性别特异性的身份，卵母细胞基因组的完整性，卵母细胞基因表达，减数分裂，和植入前发育能力的维护。
Significance MTOR (mechanistic target of rapamycin), an integrator of pathways important for cellular metabolism, proliferation, and differentiation, is expressed at all stages of oocyte development. Primordial oocytes constitute a nonproliferating, nongrowing reserve of potential eggs maintained for the entire reproductive lifespan of mammalian females. Using conditional knockouts, we determined the role of MTOR in both primordial and growing oocytes. MTOR-dependent pathways in primordial oocytes are not needed to sustain the viability of the primordial oocyte pool or their recruitment into the cohort of growing oocytes but are essential later for maintenance of oocyte genomic integrity, sustaining ovarian follicular development, and fertility. In growing oocytes, MTOR-dependent pathways are required for processes that promote completion of meiosis and enable embryonic development. MTOR (mechanistic target of rapamycin) is a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation. Here we show that conditional knockout (cKO) of Mtor in either primordial or growing oocytes caused infertility but differentially affected oocyte quality, granulosa cell fate, and follicular development. cKO of Mtor in nongrowing primordial oocytes caused defective follicular development leading to progressive degeneration of oocytes and loss of granulosa cell identity coincident with the acquisition of immature Sertoli cell-like characteristics. Although Mtor was deleted at the primordial oocyte stage, DNA damage accumulated in oocytes during their later growth, and there was a marked alteration of the transcriptome in the few oocytes that achieved the fully grown stage. Although oocyte quality and fertility were also compromised when Mtor was deleted after oocytes had begun to grow, these occurred without overtly affecting folliculogenesis or the oocyte transcriptome. Nevertheless, there was a significant change in a cohort of proteins in mature oocytes. In particular, down-regulation of PRC1 (protein regulator of cytokinesis 1) impaired completion of the first meiotic division. Therefore, MTOR-dependent pathways in primordial or growing oocytes differentially affected downstream processes including follicular development, sex-specific identity of early granulosa cells, maintenance of oocyte genome integrity, oocyte gene expression, meiosis, and preimplantation developmental competence.
登录
查看更多内容
DOI：
10.1073/pnas.95.23.13612
发表时间：
1998-11-10
影响因子：
11.1
作者：
Dierich, A;Sairam, MR;Sassone-Corsi, P
通讯作者：
Sassone-Corsi, P
DOI：
10.1002/wdev.294
发表时间：
2018-01
期刊：
Wiley interdisciplinary reviews. Developmental biology
影响因子：
--
作者：
Clarke HJ
通讯作者：
Clarke HJ
影响因子：
10.5
作者：
Duggavathi, Rajesha;Volle, David H.;Schoonjans, Kristina
通讯作者：
Schoonjans, Kristina
影响因子：
4.8
作者：
Guigon, CJ;Coudouel, N;Magre, S
通讯作者：
Magre, S
影响因子：
64.8
作者：
ITO, E;TOKI, T;YAMAMOTO, M
通讯作者：
YAMAMOTO, M