Focused screening of mitochondrial metabolism reveals a crucial role for a tumor suppressor Hbp1 in ovarian reserve.
Focused screening of mitochondrial metabolism reveals a crucial role for a tumor suppressor Hbp1 in ovarian reserve.
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线粒体代谢的集中筛查揭示了肿瘤抑制因子 Hbp1 在卵巢储备中的关键作用
DOI：
10.1038/cdd.2016.47
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发表时间：
2016-10
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
颗粒细胞(GC)与生育和卵泡的命运密切相关。线粒体是细胞凋亡的中心执行者。然而，卵巢发育过程中GCs线粒体调控的遗传基础尚不清楚。在这里，使用CRISPR/Cas9介导的遗传筛选来鉴定人类GC中与线粒体代谢相关的基因。结果揭示了包括HBP1在内的几种肿瘤抑制因子在线粒体功能增强中的作用。聚焦分析表明，高迁移率族(HMG)盒转录因子1(Hbp1)水平调节线粒体的生物发生，这与包括Tfam在内的全球转录变化有关。全身性或颗粒特异性但非卵母细胞特异性的Hbp1消融促进了卵泡生长和卵母细胞的产生，并与小鼠GC中凋亡信号的减少有关。与线粒体功能增强和GC凋亡减弱一致，Hbp1的调节对卵巢储备具有实质性的保护作用。因此，本研究的结果为理解生殖寿命的控制提供了一个重要的目标。
Granulosa cells (GCs) are tightly associated with fertility and the fate of ovarian follicles. Mitochondria are the central executers of apoptosis. However, the genetic basis underlying mitochondrial modulation in GCs during the ovarian development is poorly understood. Here, CRISPR/Cas9-mediated genetic screening was used to identify genes conferring mitochondrial metabolism in human GCs. The results uncovered roles for several tumor suppressors, including HBP1, in the augmentation of mitochondrial function. Focused analysis revealed that high-mobility group (HMG)-box transcription factor 1 (Hbp1) levels regulate mitochondrial biogenesis, which is associated with global changes in transcription including Tfam. The systemic or granulosa-specific but not oocyte-specific ablation of Hbp1 promoted follicle growth and oocyte production, and is associated with the reduced apoptotic signals in mouse GCs. Consistent with increased mitochondrial function and attenuated GC apoptosis, the regulation of Hbp1 conferred substantial protection of ovarian reserve. Thus, the results of the present study provide a critical target to understand the control of the reproductive lifespan.
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DOI：
10.1126/science.1171396
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fan HY;Liu Z;Shimada M;Sterneck E;Johnson PF;Hedrick SM;Richards JS
通讯作者：
Richards JS
影响因子：
64.8
作者：
Johnson, J;Canning, J;Tilly, JL
通讯作者：
Tilly, JL
影响因子：
4.8
作者：
HUGHES, FM;GOROSPE, WC
通讯作者：
GOROSPE, WC
影响因子：
56.9
作者：
Reddy, Pradeep;Liu, Lian;Liu, Kui
通讯作者：
Liu, Kui
影响因子：
3.5
作者：
Ekstrand, MI;Falkenberg, M;Larsson, NG
通讯作者：
Larsson, NG