Age-Related Meiotic Segregation Errors in Mammalian Oocytes Are Preceded by Depletion of Cohesin and Sgo2
Age-Related Meiotic Segregation Errors in Mammalian Oocytes Are Preceded by Depletion of Cohesin and Sgo2
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DOI：
10.1016/j.cub.2010.08.023
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发表时间：
2010-09-14
期刊：
影响因子：
9.2
通讯作者：
Herbert, Mary
中科院分区：
文献类型：
--
作者：
Lister, Lisa Martine;Kouznetsova, Anna;Herbert, Mary
背景：女性推迟生育的趋势日益明显，导致三体妊娠的发生率急剧增加。母亲年龄相关的流产和出生缺陷主要是第一次减数分裂 (MI) 期间染色体分离错误的结果，其中涉及复制重组同源染色体的分离。尽管对人类生殖健康很重要，但引发女性年龄相关减数分裂错误的事件却知之甚少。结果：在这里，我们使用长寿的野生型小鼠品系来证明，在 MI 后期同步分离染色体的能力在雌性衰老过程中急剧下降。在此之前，与染色体相关的粘连蛋白的耗尽与交叉的不稳定、同源染色体之间的物理连接以及姐妹着丝粒之间的紧密关联的丧失有关。粘连蛋白的丧失并不是由于年龄相关的纺锤体检查点延迟分离酶介导的粘连蛋白裂解直到进入后期 I 的能力下降所致。然而，我们发现粘连蛋白的减少伴随着 Sgo2 的消耗，Sgo2 在 MI 期间保护着丝粒粘连蛋白。结论：数据表明，在女性 MI 之前的长期前期停滞期间，粘连蛋白逐渐下降 哺乳动物。在老化的卵母细胞中，粘连蛋白水平低于稳定交叉和将姐妹着丝粒紧密结合在一起所需的水平，导致 MI 期间染色体错误分离。着丝粒粘连蛋白保护蛋白 Sgo2 水平的同时下降可能会加剧粘连蛋白的损失。这些发现表明，粘连蛋白是女性衰老和心肌梗死期间染色体错误分离之间的关键分子联系。
Background: The growing trend for women to postpone childbearing has resulted in a dramatic increase in the incidence of trisomic pregnancies. Maternal age-related miscarriage and birth defects are predominantly a consequence of chromosome segregation errors during the first meiotic division (MI), which involves the segregation of replicated recombined homologous chromosomes. Despite the importance to human reproductive health, the events precipitating female age-related meiotic errors are poorly understood. Results: Here we use a long-lived wild-type mouse strain to show that the ability to segregate chromosomes synchronously during anaphase of MI declines dramatically during female aging. This is preceded by depletion of chromosome-associated cohesin in association with destabilization of chiasmata, the physical linkages between homologous chromosomes, and loss of the tight association between sister centromeres. Loss of cohesin is not due to an age-related decline in the ability of the spindle checkpoint to delay separase-mediated cleavage of cohesin until entry into anaphase I. However, we find that reduced cohesin is accompanied by depletion of Sgo2, which protects centromeric cohesin during MI.Conclusions: The data indicate that cohesin declines gradually during the long prophase arrest that precedes MI in female mammals. In aged oocytes, cohesin levels fall below the level required to stabilize chiasmata and to hold sister centromeres tightly together, leading to chromosome missegregation during MI. Cohesin loss may be amplified by a concomitant decline in the levels of the centromeric cohesin protector Sgo2. These findings indicate that cohesin is a key molecular link between female aging and chromosome missegregation during MI.