Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes.
Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes.
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DOI：
10.1016/j.cub.2010.06.069
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发表时间：
2010-09-14
期刊：
影响因子：
9.2
通讯作者：
Lampson, Michael A.
中科院分区：
文献类型：
--
作者：
Chiang, Teresa;Duncan, Francesca E.;Schindler, Karen;Schultz, Richard M.;Lampson, Michael A.
发育早期出现的非整倍体是人类出生缺陷和发育障碍的主要原因。大多数染色体数目错误源自卵子，而母亲年龄已被确定为关键风险因素。尽管这一问题对生殖健康的重要性已得到广泛认可，但女性减数分裂中与年龄相关的非整倍性的潜在分子基础尚不清楚。在这里，我们表明，染色体凝聚力减弱是自然衰老小鼠模型中卵母细胞非整倍性的主要原因。我们发现姐妹着丝粒在中期 I 和 II 都相距较远，表明着丝粒内聚力降低。此外，老年小鼠卵母细胞染色体上减数分裂粘连蛋白REC8的水平严重降低。为了测试内聚缺陷是否会导致观察到的非整倍体，我们监测了活卵母细胞后期 I 的染色体分离动态，并对所得中期 II 卵中的染色体进行了计数。大约 90% 的与年龄相关的非整倍体最好用着丝粒内聚力减弱来解释。总之，这些结果表明，与母亲年龄相关的非整倍体增加通常是由于未能有效替换衰老过程中从染色体中丢失的粘连蛋白所致。
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.
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