Meiosis and Maternal Aging: Insights from Aneuploid Oocytes and Trisomy Births

Herbert, Mary; Kalleas, Dimitrios; Cooney, Daniel B.; Lamb, Mahdi; Lister, Lisa

doi:10.1101/cshperspect.a017970

Cited by 181 publications

(188 citation statements)

References 127 publications

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“…The hypothesis that deterioration of meiotic cohesion over a woman's lifetime contributes to the maternal age effect has gained considerable support over the last decade (9,10). One reason this theory is attractive is that in human oocytes, cohesion is established and meiotic recombination is completed during early fetal development.…”

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confidence: 99%

Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors

Perkins

Das

Panzera

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In humans, errors in meiotic chromosome segregation that produce aneuploid gametes increase dramatically as women age, a phenomenon termed the "maternal age effect." During meiosis, cohesion between sister chromatids keeps recombinant homologs physically attached and premature loss of cohesion can lead to missegregation of homologs during meiosis I. A growing body of evidence suggests that meiotic cohesion deteriorates as oocytes age and contributes to the maternal age effect. One hallmark of aging cells is an increase in oxidative damage caused by reactive oxygen species (ROS). Therefore, increased oxidative damage in older oocytes may be one of the factors that leads to premature loss of cohesion and segregation errors. To test this hypothesis, we used an RNAi strategy to induce oxidative stress in Drosophila oocytes and measured the fidelity of chromosome segregation during meiosis. Knockdown of either the cytoplasmic or mitochondrial ROS scavenger superoxide dismutase (SOD) caused a significant increase in segregation errors, and heterozygosity for an smc1 deletion enhanced this phenotype. FISH analysis indicated that SOD knockdown moderately increased the percentage of oocytes with arm cohesion defects. Consistent with premature loss of arm cohesion and destabilization of chiasmata, the frequency at which recombinant homologs missegregate during meiosis I is significantly greater in SOD knockdown oocytes than in controls. Together these results provide an in vivo demonstration that oxidative stress during meiotic prophase induces chromosome segregation errors and support the model that accelerated loss of cohesion in aging human oocytes is caused, at least in part, by oxidative damage. meiosis | maternal age effect | oxidative damage | reactive oxygen species | superoxide dismutase C hromosome segregation errors during female meiosis are the leading cause of birth defects and miscarriages in humans and their incidence increases dramatically with age (1). Over 90% of Down syndrome cases are the result of an extra copy of chromosome 21 inherited from the mother (2). Although the probability of a meiotic missegregation event is relatively low during a woman's twenties, by the time she reaches her early forties, she has a one in three chance of conceiving an aneuploid fetus (3). Work in the last decade has begun to shed light on the molecular mechanisms that underlie this phenomenon known as the "maternal age effect."Proper chromosome segregation during both mitosis and meiosis requires that physical linkages between sister chromatids (cohesion) be formed, maintained, and released in a regulated manner (4, 5). Sister chromatid cohesion, mediated by the evolutionarily conserved cohesin complex, is established during DNA replication. During meiosis, in addition to holding sister chromatids together, cohesion is required to maintain the physical association of recombinant homologs and is therefore essential for proper segregation during the first as well as the second meiotic division (6-8). Normally, a crossover ...

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confidence: 99%

Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors

Perkins

Das

Panzera

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The overall high aneuploidy rates are increasing further with maternal age, at least in human and mouse oocytes [Eichenlaub-Ritter, 2012;Nagaoka et al, 2012;Jones and Lane, 2013;Herbert et al, 2015], although for example porcine oocytes do not show a similar age-related increase in aneuploidy [Hornak et al, 2011]. Despite the fact that we can explain the increase of aneuploidy coincidently with maternal age by deterioration of cohesion between sister chromatids [Chiang et al, 2010;Lister et al, 2010] due to the absence of turnover of the cohesin complex during a prolonged prophase arrest [Revenkova et al, 2010;Tachibana-Konwalski et al, 2010], we are still uncertain why the aneuploidy is so high even in oocytes from young individuals in comparison to meiosis in yeast and Drosophila [Hassold and Hunt, 2001].…”

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confidence: 99%

True Nondisjunction of Whole Bivalents in Oocytes with Attachment and Congression Defects

Šodek

Kovacovicova

Anger

2017

Cytogenet Genome Res

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Chromosome segregation in mammalian oocytes is prone to errors causing aneuploidy with consequences such as precocious termination of development or severe developmental disorders. Aneuploidy also represents a serious problem in procedures utilizing mammalian gametes and early embryos in vitro. In our study, we focused on congression defects during meiosis I and observed whole nondisjoined bivalents in meiosis II as a direct consequence, together with a substantially delayed first polar body extrusion. We also show that the congression defects are accompanied by less stable attachments of the kinetochores. Our results describe a process by which congression defects directly contribute to aneuploidy.

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“…In mice, as in other mammals, female meiosis initiates during fetal development [6,22]. Oocytes complete the chromosome pairing and recombination steps of meiotic prophase prior to birth, then enter a prolonged period of arrest (the dictyate stage) and coordinate with surrounding somatic cells during the first few days after birth to form follicles [6,22]. Primordial follicles are the resting pool of germ cells that will be recruited for further development and ovulation during the reproductive life of the animal [6,22].…”

Section: Cyclin B3 Is Required For the Metaphase-to-anaphase I Transimentioning

confidence: 99%

“…Oocytes complete the chromosome pairing and recombination steps of meiotic prophase prior to birth, then enter a prolonged period of arrest (the dictyate stage) and coordinate with surrounding somatic cells during the first few days after birth to form follicles [6,22]. Primordial follicles are the resting pool of germ cells that will be recruited for further development and ovulation during the reproductive life of the animal [6,22]. Ovary sections from Ccnb3 -/-females showed abundant oocytes in primordial and growing follicles at 2-3 months of age, and were quantitatively and morphologically indistinguishable from littermate controls ( Figure 1C).…”

Section: Cyclin B3 Is Required For the Metaphase-to-anaphase I Transimentioning

confidence: 99%

Cyclin B3 promotes APC/C activation and anaphase I onset in oocyte meiosis

Bouftas

Keeney

et al. 2018

Preprint

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As obligate kinase partners, cyclins control the switch-like cell cycle transitions that orchestrate orderly duplication and segregation of genomes. Meiosis, the cell division that generates gametes for sexual reproduction, poses unique challenges because two rounds of chromosome segregation must be executed without intervening DNA replication. Mammalian cells express numerous, temporally regulated cyclins, but how these proteins collaborate to control meiosis remains poorly understood. Here, we delineate an essential function for mouse cyclin B3 in the first meiotic division of oocytes. Females genetically ablated for cyclin B3 are viable, indicating the protein is dispensable for mitotic divisions, but are sterile. Mutant oocytes appear normal until metaphase I but then display a highly penetrant failure to transition to anaphase I. They arrest with hallmarks of defective APC/C activation, including no separase activity and high MPF, cyclin B1, and securin levels. Partial APC/C activation occurs, however, as exogenously expressed APC/C substrates can be degraded and arrest can be suppressed by inhibiting MPF kinase. Cyclin B3 is itself targeted for degradation by the APC/C. Cyclin B3 forms active kinase complexes with CDK1, and meiotic progression requires cyclin B3-associated kinase activity. Collectively, our findings indicate that cyclin B3 is essential for oocyte meiosis because it fine-tunes APC/C activity as a kinase-activating CDK partner. Cyclin B3 homologs from frog, zebrafish, and fruitfly rescue meiotic progression in cyclin B3-deficient mouse oocytes, indicating conservation of the biochemical properties and possibly cellular functions of this germline-critical cyclin. IntroductionEukaryotic cell division depends on oscillations of cyclindependent kinases (CDKs) associated with specific cyclins [1][2][3][4]. In vertebrate somatic cells, progression from G1 into S phase, G2, and mitosis depends on the cyclin D family, followed by the cyclin E, A, and B families [4]. Ordered CDK activity likewise governs progression through meiosis: chromosome condensation, congression, and alignment require a rise in cyclin B-CDK1 activity, then anaphase onset and chromosome segregation are driven by sudden inactivation of cyclin B-CDK1 by the anaphase promoting complex/ cyclosome (APC/C), an E3 ubiquitin ligase that targets substrates for degradation by the 26S proteasome [5]. Cyclin B-CDK1 activity re-accumulates following its depletion, but meiotic cells have the challenge of not inducing DNA replication during the period of low cyclin B-CDK1 activity between meiosis I and II [6,7]. The roles of specific cyclins in shaping CDK oscillations and thus in determining the orderly progression of meiosis remain poorly understood, particularly in mammalian oocytes.In this context, cyclin B3 is particularly enigmatic. Cyclin B3 belongs to a separate family with characteristics of both A-and B-type cyclins [8,9] and is evolutionarily conserved from early metazoans to human [10]. Ciona intestinalis cyclin B3 counteracts zyg...

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Meiosis and Maternal Aging: Insights from Aneuploid Oocytes and Trisomy Births

Cited by 181 publications

References 127 publications

Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors

Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors

True Nondisjunction of Whole Bivalents in Oocytes with Attachment and Congression Defects

Cyclin B3 promotes APC/C activation and anaphase I onset in oocyte meiosis

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