Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice

Guo, Jing; Zhang, Teng; Guo, Yueshuai; Sun, Tao; Li, Hui; Zhang, Xiaoyun; Yin, Hong; Cao, Guangyi; Yin, Yaoxue; Wang, Hao; Shi, Lei; Guo, Xuejiang; Sha, Jiahao; Eppig, John J.; Su, You-Qiang

doi:10.1073/pnas.1800352115

Cited by 127 publications

(106 citation statements)

References 58 publications

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“…Recent evidence implicates metabolic pathways as important regulators of meiotic progression and gametogenesis (Chi et al, 2016;Ferguson, Blundon, Klovstad, & Schupbach, 2012;Guo et al, 2018;LaFever, Feoktistov, Hsu, & Drummond-Barbosa, 2010;Sieber, Thomsen, & Spradling, 2016). Here we define a role for the GATOR complex, a conserved regulator of TORC1 activity, in the regulation of two events that impact germline genome stability: the response to meiotic DSBs and the inhibition of retrotransposon expression.…”

Section: Discussionmentioning

confidence: 95%

The GATOR complex regulates an essential response to meiotic double-stranded breaks inDrosophila

Wei

Bettedi

Kim

et al. 2018

Preprint

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The TORC1 inhibitor GATOR1/SEACIT controls meiotic entry and early meiotic events in yeast. However, how metabolic pathways influence meiotic progression in metazoans remains poorly understood. Here we report that the TORC1 regulators GATOR1 and GATOR2 mediate a response to meiotic double-stranded breaks (DSBs) during Drosophila oogenesis. We find that meiotic DSBs trigger the activation of a GATOR1 dependent pathway that downregulates TORC1 activity in the female germline. In GATOR1 mutants, high TORC1 activity results in the delayed repair of meiotic DSBs and the hyperactivation of p53. Conversely, the GATOR2 component Mio is required to attenuate GATOR1 activity, to ensure that meiotic DSBs do not trigger a permanent growth arrest. Unexpectedly, we found that GATOR1 inhibits retrotransposon expression in the presence of meiotic DSBs in a pathway that functions in parallel to p53. Our studies have revealed a link between the GATOR complex, the repair of meiotic DSBs and retrotransposon expression

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Section: Discussionmentioning

confidence: 95%

The GATOR complex regulates an essential response to meiotic double-stranded breaks inDrosophila

Wei

Bettedi

Kim

et al. 2018

Preprint

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“…BCAR4 was also reported to promote chondrosarcoma cell proliferation through activation of mTOR 19 , a downstream target of ERBB2/ERBB3 signalling. Some features of the phenotype of BCAR4-deficient rabbits are reminiscent of the impact of oocyte-targeted mTor knock-out (KO) in mouse 20 . Abrogating mTor expression from the primary follicle stage onwards did not affect follicular development up to the preovulatory stage.…”

Section: Discussionmentioning

confidence: 99%

Investigating the role of BCAR4 in ovarian physiology and female fertility by genome editing in rabbit

Peyny

Jarrier-Gaillard

Boulanger

et al. 2020

Sci Rep

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Breast Cancer Anti-estrogen Resistance 4 (BCAR4) was previously characterised in bovine species as a gene preferentially expressed in oocytes, whose inhibition is detrimental to in vitro embryo development. But its role in oogenesis, folliculogenesis and globally fertility in vivo remains unknown. Because the gene is not conserved in mice, rabbits were chosen for investigation of BCAR4 expression and function in vivo. BCAR4 displayed preferential expression in the ovary compared to somatic organs, and within the ovarian follicle in the oocyte compared to somatic cells. the transcript was detected in follicles as early as the preantral stage. Abundance decreased throughout embryo development until the blastocyst stage. A lineage of genome-edited rabbits was produced; BCAR4 expression was abolished in follicles from homozygous animals. females of wild-type, heterozygous and homozygous genotypes were examined for ovarian physiology and reproductive parameters. follicle growth and the number of ovulations in response to hormonal stimulation were not significantly different between genotypes. Following insemination, homozygous females displayed a significantly lower delivery rate than their heterozygous counterparts (22 ± 7% vs 71 ± 11% (mean ± SEM)), while prolificacy was 1.8 ± 0.7 vs 6.0 ± 1.4 kittens per insemination. In conclusion, BCAR4 is not essential for follicular growth and ovulation but it contributes to optimal fertility in rabbits. open Scientific RepoRtS | (2020) 10:4992 | https://doi.

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“…Interestingly, PRC1 is downregulated in Mtor-ZcKO oocytes. Taking the role of PRC1 (protein regulating cytokinesis 1) in the control of somatic cell cytokinesis division into account, a reduced level of its expression in oocytes may indicate that they have reached maturity [44]. From the group of 10 selected downregulated genes, the expression of EREG (epiregulin) decreased the most.…”

Section: Discussionmentioning

confidence: 99%

Human Ovarian Granulosa Cells Isolated during an IVF Procedure Exhibit Differential Expression of Genes Regulating Cell Division and Mitotic Spindle Formation

Brązert

Kranc

Chermuła

et al. 2019

JCM

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Granulosa cells (GCs) are a population of somatic cells whose role after ovulation is progesterone production. GCs were collected from patients undergoing controlled ovarian stimulation during an in vitro fertilization procedure, and they were maintained for 1, 7, 15, and 30 days of in vitro primary culture before collection for further gene expression analysis. A study of genes involved in the biological processes of interest was carried out using expression microarrays. To validate the obtained results, Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) was performed. The direction of changes in the expression of the selected genes was confirmed in most of the examples. Six ontological groups (“cell cycle arrest”, “cell cycle process”, “mitotic spindle organization”, “mitotic spindle assembly checkpoint”, “mitotic spindle assembly”, and “mitotic spindle checkpoint”) were analyzed in this study. The results of the microarrays obtained by us allowed us to identify two groups of genes whose expressions were the most upregulated (FAM64A, ANLN, TOP2A, CTGF, CEP55, BIRC5, PRC1, DLGAP5, GAS6, and NDRG1) and the most downregulated (EREG, PID1, INHA, RHOU, CXCL8, SEPT6, EPGN, RDX, WNT5A, and EZH2) during the culture. The cellular ultrastructure showed the presence of structures characteristic of mitotic cell division: a centrosome surrounded by a pericentric matrix, a microtubule system, and a mitotic spindle connected to chromosomes. The main goal of the study was to identify the genes involved in mitotic division and to identify the cellular ultrastructure of GCs in a long-term in vitro culture. All of the genes in these groups were subjected to downstream analysis, and their function and relation to the ovarian environment are discussed. The obtained results suggest that long-term in vitro cultivation of GCs may lead to their differentiation toward another cell type, including cells with cancer-like characteristics.

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Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice

Cited by 127 publications

References 58 publications

The GATOR complex regulates an essential response to meiotic double-stranded breaks inDrosophila

The GATOR complex regulates an essential response to meiotic double-stranded breaks inDrosophila

Investigating the role of BCAR4 in ovarian physiology and female fertility by genome editing in rabbit

Human Ovarian Granulosa Cells Isolated during an IVF Procedure Exhibit Differential Expression of Genes Regulating Cell Division and Mitotic Spindle Formation

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