Why is Chromosome Segregation Error in Oocytes Increased With Maternal Aging?

Wang, Zhenbo; Schatten, Heide; Sun, Qing‐Yuan

doi:10.1152/physiol.00020.2011

Cited by 32 publications

(24 citation statements)

References 133 publications

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“…It is estimated that 20% of human oocytes are aneuploid, and mistakes in meiotic chromosome segregation account for one third of all pregnancy losses (Hassold and Hunt, 2001;Qiao et al, 2014;Wang et al, 2011). Both MI and MII exits are key events in maintaining the euploidy of oocytes.…”

Section: Discussionmentioning

confidence: 99%

Loss of protein phosphatase 6 in oocytes causes failure of meiosis II exit and impaired female fertility

Wang

Teng³

et al. 2015

Journal of Cell Science

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Dynamic protein phosphorylation and dephosphorylation, mediated by a conserved cohort of protein kinases and phosphatases, regulate cell cycle progression. Among the well-known PP2A-like protein phosphatases, protein phosphatase 6 (PP6) has been analyzed in mammalian mitosis, and Aurora A has recently been identified as its key substrate. However, the functions of PP6 in meiosis are still entirely unknown. To identify the physiological role of PP6 in female gametogenesis, Ppp6c F/F mice were first generated and crossed with Zp3-Cre mice to selectively disrupt Ppp6c expression in oocytes. Here, we report for the first time that PP6c is dispensable for oocyte meiotic maturation but essential for exit from meiosis II (MII) after fertilization. Depletion of PP6c caused an abnormal MII spindle and disrupted MII cytokinesis, resulting in zygotes with high risk of aneuploidy and defective early embryonic development, and thus severe subfertility. We also reveal that PP6 inactivation interferes with MII spindle formation and MII exit owing to increased Aurora A activity, and that Aurora A inhibition with MLN8237 can rescue the PP6c depletion phenotype. In conclusion, our findings uncover a hitherto unknown role for PP6 as an indispensable regulator of oocyte meiosis and female fertility.

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Section: Discussionmentioning

confidence: 99%

Loss of protein phosphatase 6 in oocytes causes failure of meiosis II exit and impaired female fertility

Wang

Teng³

et al. 2015

Journal of Cell Science

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“…DNA damage at telomeres could contribute to telomere attrition, contributing to non-disjunction, miscarriage and Downs syndrome [14][15][16]. Old mouse oocytes show shorter telomeres than those of young oocytes [17].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey

Zhang

Zeng

et al. 2015

J Assist Reprod Genet

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Purpose Ovarian aging is closely tied to the decline in ovarian follicular reserve and oocyte quality. During the prolonged reproductive lifespan of the female, granulosa cells connected with oocytes play critical roles in maintaining follicle reservoir, oocyte growth and follicular development. We tested whether double-strand breaks (DSBs) and repair in granulosa cells within the follicular reservoir are associated with ovarian aging. Methods Ovaries were sectioned and processed for epifluorescence microscopy, confocal microscopy, and immunohistochemistry. DNA damage was revealed by immunstaining of γH2AX foci and telomere damage by γH2AX foci colocalized with telomere associated protein TRF2. DNA repair was indicated by BRCA1 immunofluorescence.Results DSBs in granulosa cells increase and DSB repair ability, characterized by BRCA1 foci, decreases with advancing age. γH2AX foci increase in primordial, primary and secondary follicles with advancing age. Likewise, telomere damage increases with advancing age. In contrast, BRCA1 foci in granulosa cells of primordial, primary and secondary follicles decrease with monkey age. BRCA1 positive foci in the oocyte nuclei also decline with maternal age. Conclusions Increased DSBs and reduced DNA repair in granulosa cells may contribute to ovarian aging. Discovery of therapeutics that targets these pathways might help maintain follicle reserve and postpone ovarian dysfunction with age.

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“…Previously, we and others have fully reviewed the cellular and molecular alterations as well as the mechanisms underlying oocyte aging [1, 2,6,7]. The protein profiles during porcine oocyte aging have also been investigated by us [30].…”

Section: Special Topicmentioning

confidence: 99%

“…It has been well established that a decline in female fertility with increasing maternal age is due to high frequency of errors in meiotic chromosome segregation during female meiosis [1,2]. Studies suggested that defects in deacetylation at some histone lysine residues in old oocyte may be involved.…”

Section: Epigenetic Changes: Underlying Mechanisms Of Oocyte Agingmentioning

confidence: 99%

“…Female germ cell meiosis is a long and extremely complex process, characterized by two consecutive cell divisions (meiosis I and II) and two cell cycle arrests: at the dictyate stage of prophase I (the germinal vesicle stage), and at metaphase II [1,2]. During the meiotic process, a series of changes of nuclear and cytoplasmic events take place to prepare the oocytes to obtain fertilization and subsequent developmental potentials.…”

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Epigenetic changes associated with oocyte aging

Liang

Schatten

et al. 2012

Sci. China Life Sci.

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It is well established that the decline in female reproductive outcomes is related to postovulatory aging of oocytes and advanced maternal age. Poor oocyte quality is correlated with compromised genetic integrity and epigenetic changes during the oocyte aging process. Here, we review the epigenetic alterations, mainly focused on DNA methylation, histone acetylation and methylation associated with postovulatory oocyte aging as well as advanced maternal age. Furthermore, we address the underlying epigenetic mechanisms that contribute to the decline in oocyte quality during oocyte aging.

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Why is Chromosome Segregation Error in Oocytes Increased With Maternal Aging?

Cited by 32 publications

References 133 publications

Loss of protein phosphatase 6 in oocytes causes failure of meiosis II exit and impaired female fertility

Loss of protein phosphatase 6 in oocytes causes failure of meiosis II exit and impaired female fertility

Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey

Epigenetic changes associated with oocyte aging

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