Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B.
Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B.
复制标题
DOI：
10.1111/acel.13489
复制
发表时间：
2021-11
期刊：
影响因子：
7.8
通讯作者：
Schindler K
中科院分区：
文献类型：
--
作者：
Blengini CS;Nguyen AL;Aboelenain M;Schindler K
高龄产妇的一个标志是减数分裂染色体分离错误显着增加，导致早期流产和先天性疾病。这些错误最常发生在减数分裂 I (MI) 期间。纺锤体装配检查点 (SAC) 通过阻止细胞周期直至实现正确的染色体排列来防止染色体分离错误。与有丝分裂不同，卵母细胞中的 SAC 是脱敏的，允许在存在不正确排列的染色体的情况下进行染色体分离。 SAC 完整性是否会随着母亲年龄的增长而进一步恶化，以及这种下降是否会导致分离错误增加，仍然是一个基本问题。在体细胞中，SAC 的激活取决于极光激酶 B (AURKB)，其功能是监测动粒-微管附着并招募 SAC 调节蛋白。在小鼠中，卵母细胞特异性缺失 AURKB (Aurkb cKO) 会导致非整倍体中期 II 停滞卵的产生增加以及与年龄相关的过早不孕。在这里，我们旨在了解生殖寿命短的原因，并假设 SAC 完整性受到损害。在比较年轻和性成熟 Aurkb cKO 雌性的卵母细胞时，我们发现 SAC 完整性随着母亲年龄的增长而迅速受到损害。我们发现，SAC 脱敏的增加是由 MAD2、ZW10 和 Securin 蛋白表达减少驱动的，这些蛋白是 SAC 反应途径的关键贡献者。这些蛋白质表达的减少是蛋白质稳态改变的结果，可能是由活性氧的积累引起的。总而言之，我们的结果证明了 AURKB 可能通过保护卵母细胞免受氧化应激来维持女性生殖寿命的新功能。 AURKB 可能需要通过保护卵母细胞免受氧化应激来维持女性生殖寿命。我们发现 Aurkb KO 卵母细胞在母体衰老过程中过早积累 ROS。来自老年雌性的前期停滞卵母细胞的 SAC 信号成分表达减少，导致减数分裂 I 期间 SAC 反应减弱。我们认为这些蛋白质表达的减少是由于 ROS 积累引起的蛋白质稳态改变的结果。
A hallmark of advanced maternal age is a significant increase in meiotic chromosome segregation errors, resulting in early miscarriages and congenital disorders. These errors most frequently occur during meiosis I (MI). The spindle assembly checkpoint (SAC) prevents chromosome segregation errors by arresting the cell cycle until proper chromosome alignment is achieved. Unlike in mitosis, the SAC in oocytes is desensitized, allowing chromosome segregation in the presence of improperly aligned chromosomes. Whether SAC integrity further deteriorates with advancing maternal age, and if this decline contributes to increased segregation errors remains a fundamental question. In somatic cells, activation of the SAC depends upon Aurora kinase B (AURKB), which functions to monitor kinetochore–microtubule attachments and recruit SAC regulator proteins. In mice, oocyte‐specific deletion of AURKB (Aurkb cKO) results in an increased production of aneuploid metaphase II‐arrested eggs and premature age‐related infertility. Here, we aimed to understand the cause of the short reproductive lifespan and hypothesized that SAC integrity was compromised. In comparing oocytes from young and sexually mature Aurkb cKO females, we found that SAC integrity becomes compromised rapidly with maternal age. We show that the increased desensitization of the SAC is driven by reduced expression of MAD2, ZW10 and Securin proteins, key contributors to the SAC response pathway. The reduced expression of these proteins is the result of altered protein homeostasis, likely caused by the accumulation of reactive oxygen species. Taken together, our results demonstrate a novel function for AURKB in preserving the female reproductive lifespan possibly by protecting oocytes from oxidative stress. AURKB in needed to preserve the female reproductive lifespan likely by protecting oocytes from oxidative stress. We show that Aurkb KO oocytes prematurely accumulate ROS during maternal aging. Prophase‐arrested oocytes from older females have reduced expression of SAC signaling components, causing a weakened SAC response during meiosis I. We propose the reduced expression of these proteins is the result of altered protein homeostasis, caused by the accumulation of ROS.
登录
查看更多内容
影响因子：
4.4
作者：
Bertolin G;Alves-Guerra MC;Cheron A;Burel A;Prigent C;Le Borgne R;Tramier M
通讯作者：
Tramier M
影响因子：
5.8
作者：
Grant R;Abdelbaki A;Bertoldi A;Gavilan MP;Mansfeld J;Glover DM;Lindon C
通讯作者：
Lindon C
影响因子：
13.3
作者：
May-Panloup, Pascale;Boucret, Lisa;Reynier, Pascal
通讯作者：
Reynier, Pascal
影响因子：
4.6
作者：
Lane, Simon I. R.;Yun, Yan;Jones, Keith T.
通讯作者：
Jones, Keith T.
影响因子：
9.2
作者：
Nagaoka, So Iha;Hodges, Craig A.;Albertini, David F.;Hunt, Patricia Ann
通讯作者：
Hunt, Patricia Ann