Summary Aneuploidy arising early in development is the leading genetic cause of birth defects and developmental disabilities in humans. Most errors in chromosome number originate from the egg, and maternal age is well established as the key risk factor. Although the importance of this problem for reproductive health is widely recognized, the underlying molecular basis for age-related aneuploidy in female meiosis is unknown. Here we show that weakened chromosome cohesion is a leading cause of aneuploidy in oocytes in a natural aging mouse model. We find that sister kinetochores are farther apart at both Metaphase I and II, indicating reduced centromere cohesion. Moreover, levels of the meiotic cohesin protein REC8 are severely reduced on chromosomes in oocytes from old mice. To test whether cohesion defects lead to the observed aneuploidies, we monitored chromosome segregation dynamics at Anaphase I in live oocytes and counted chromosomes in the resulting Metaphase II eggs. About 90% of age-related aneuploidies are best explained by weakened centromere cohesion. Together, these results demonstrate that the maternal age-associated increase in aneuploidy is often due to a failure to effectively replace cohesin proteins that are lost from chromosomes during aging.
Chromosome segregation errors in female meiosis lead to aneuploidy in the resulting egg and embryo, making them one of the leading genetic causes of spontaneous abortions and developmental disabilities in humans. It is known that aneuploidy of meiotic origin increases dramatically as women age, and current evidence suggests that most errors occur in meiosis I. Several hypotheses regarding the cause of maternal age-related aneuploidy have been proposed, including recombination errors in early meiosis, a defective spindle assembly checkpoint in meiosis I, and deterioration of sister chromatid cohesion with age. This review discusses findings in each area, and focuses especially on recent studies suggesting that deterioration of cohesion with increasing maternal age is a leading cause of age-related aneuploidy.
Advanced maternal age is unequivocally associated with increased aneuploidy in human eggs and infertility, but the molecular basis for this phenomenon is unknown. An age-dependent deterioration of the spindle assembly checkpoint (SAC) has been proposed as a probable cause of aneuploidy. Accurate chromosome segregation depends on correct chromosome attachment to spindle microtubules, and the SAC provides time for this process by delaying anaphase onset until all chromosomes are stably attached. If SAC function decreases with age, oocytes from reproductively old mice would enter anaphase of meiosis I (AI) prematurely, leading to chromosome segregation errors and aneuploid eggs. Although intuitively appealing, this hypothesis is largely untested. We used a natural reproductive aging mouse model to determine if a defective SAC is the primary cause of aneuploidy in eggs. We tracked the progress of individual oocytes from young and old mice through meiosis I by time-lapse microscopy and counted chromosomes in the resulting eggs. This data set allowed us to correlate the timing of AI onset with aneuploidy in individual oocytes. We found that oocytes from old mice do not enter AI prematurely compared to young counterparts despite a 4-fold increase in the incidence of aneuploidy. Moreover, we did not observe a correlation between the timing of AI onset and aneuploidy in individual oocytes. When SAC function was challenged with a low concentration of the spindle toxin nocodazole, oocytes from both young and old mice arrested at meiosis I, which is indicative of a functional checkpoint. These findings indicate that a defective SAC is unlikely the primary cause of aneuploidy associated with maternal age.
A hypothesis to explain the maternal age-dependent increase in formation of aneuploid eggs is deterioration of chromosome cohesion. Although several lines of evidence are consistent with this hypothesis, whether cohesion is actually reduced in naturally aged oocytes has not been directly tested by any experimental perturbation. To directly target cohesion, we increased the activity of separase, the protease that cleaves the meiotic cohesin REC8, in oocytes. We show that cohesion is more susceptible to premature separase activation in old oocytes than in young oocytes, demonstrating that cohesion is significantly reduced. Furthermore, cohesion is protected by two independent mechanisms that inhibit separase, securin and an inhibitory phosphorylation of separase by CDK1; both mechanisms must be disrupted to prematurely activate separase. With the continual loss of cohesins from chromosomes that occurs throughout the natural reproductive lifespan, tight regulation of separase in oocytes may be particularly important to maintain cohesion and prevent aneuploidy.
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