Transient inhibition of CDK2 activity prevents oocyte meiosis I completion and egg activation in mouse
Transient inhibition of CDK2 activity prevents oocyte meiosis I completion and egg activation in mouse
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瞬时抑制 CDK2 活性可阻止小鼠卵母细胞减数分裂 I 的完成和卵子的激活
DOI：
10.1002/jcp.30885
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发表时间：
2022-09-26
影响因子：
5.6
通讯作者：
Qian，Wei-Ping
中科院分区：
文献类型：
--
作者：
Li，Jian;Chang，Hao-Ya;Qian，Wei-Ping
哺乳动物卵母细胞在胎儿或出生后发育过程中停滞在I期前期的双线期。据报道，在小鼠卵母细胞中，CDK1是唯一驱动减数分裂恢复的CDK，而CDK2对小鼠卵母细胞的减数分裂进程是必不可少的。然而，最近的一项研究表明，CDK2的活性对于减数分裂和配子发生是必不可少的，这是通过基因定向突变的方式来避免其他CDKs的补偿激活。考虑到基因敲除后CDK2活性在CDKs之间的代偿作用，CDK2在卵母细胞成熟中的生理作用尚不清楚。为了解决这个问题，我们在卵母细胞减数分裂成熟过程中应用了一种特定的小分子抑制剂来暂时抑制CDK2的活性。令人惊讶的是，对CDK2活性的短暂抑制严重阻止了减数分裂I的完成，尽管减数分裂恢复没有受到影响。然后我们发现CDK2活性是建立正常纺锤体和染色体动力学所必需的。值得注意的是，CDK2抑制通过维持纺锤体组装检查点(SAC)的激活来阻断依赖于后期促进复合体/环体(APC/C)的降解途径。有趣的是，抑制CDK2也阻止了卵子的激活。总之，我们的数据表明，CDK2激酶活性是纺锤体和染色体正常运动所必需的，它的干扰导致卵母细胞减数分裂过程中持续的SAC激活和随后的APC/C活性失活。
Mammalian oocytes are arrested at the diplotene stage of prophase I during fetal or postnatal development. It was reported that cyclin‐dependent kinases (CDK1) was the sole CDK to drive the resumption of meiosis and CDK2 was dispensable for meiosis progression in mouse oocytes according to the conditional knockout studies. However, a recent study showed that CDK2 activity is essential for meiotic division and gametogenesis by means of gene‐directed mutagenesis, which avoids the compensatory activation of other CDKs. Taken the compensatory effect between CDKs after gene knockout, the physiological function of CDK2 activity in oocyte maturation remains unclear. To address this issue, we applied a specific small‐molecule inhibitor to restrain CDK2 activity transiently during oocyte meiotic maturation. Surprisingly, transient inhibition of CDK2 activity severely prevented the meiosis I completion although the meiotic resumption was not affected. Then we found that CDK2 activity was required for establishment of normal spindle and chromosome dynamics. Notably, CDK2 inhibition interrupted the anaphase‐promoting complex/cyclosome (APC/C)‐dependent degradation pathway by maintaining the activation of spindle assembly checkpoint (SAC). Interestingly, CDK2 inhibition prevented the egg activation as well. Overall, our data demonstrate that CDK2 kinase activity is required for proper dynamics of spindle and chromosomes, whose disturbance induces the continuous SAC activation and subsequent inactivation of APC/C activity in oocyte meiosis.