Separase phosphosite mutation leads to genome instability and primordial germ cell depletion during oogenesis.
Separase phosphosite mutation leads to genome instability and primordial germ cell depletion during oogenesis.
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分离酶磷酸位点突变导致卵子发生过程中基因组不稳定和原始生殖细胞耗竭。
DOI：
10.1371/journal.pone.0018763
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发表时间：
2011-04-11
期刊：
影响因子：
3.7
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Xu J;Wang M;Gao X;Hu B;Du Y;Zhou J;Tian X;Huang X
为了确保细胞分裂过程中染色体分离和基因组的稳定性，Separase主要通过Securin结合和抑制性磷酸化进行严格调节。通过产生含有分离酶的抑制性磷酸位点突变的小鼠模型，我们证明了两种性别的小鼠都是不育的。我们发现，在胚胎卵子发生过程中，分离酶失调导致染色体错误分离，基因组不稳定，并最终导致原始生殖细胞（PGCs）凋亡。尽管突变雄性小鼠的PGC完全耗尽，但突变雌性小鼠的PGC群体在分离酶失调下存活。存活的PGCs完成卵子发生，但产生缺陷的初始卵泡。这些结果表明，PGC的性二型效应从分离酶失调，这可能与性别特异性差异的Securin。我们的研究结果表明，在卵子发生中，Separase的磷酸化调节对基因组的稳定性至关重要。此外，我们提供了第一个证据，证明分离酶失调导致合子前有丝分裂染色体分离错误，其性别特异性差异可能是配子发生中非整倍性二态性的原因。
To ensure equal chromosome segregation and the stability of the genome during cell division, Separase is strictly regulated primarily by Securin binding and inhibitory phosphorylation. By generating a mouse model that contained a mutation to the inhibitory phosphosite of Separase, we demonstrated that mice of both sexes are infertile. We showed that Separase deregulation leads to chromosome mis-segregation, genome instability, and eventually apoptosis of primordial germ cells (PGCs) during embryonic oogenesis. Although the PGCs of mutant male mice were completely depleted, a population of PGCs from mutant females survived Separase deregulation. The surviving PGCs completed oogenesis but produced deficient initial follicles. These results indicate a sexual dimorphism effect on PGCs from Separase deregulation, which may be correlated with a gender-specific discrepancy of Securin. Our results reveal that Separase phospho-regulation is critical for genome stability in oogenesis. Furthermore, we provided the first evidence of a pre-zygotic mitotic chromosome segregation error resulting from Separase deregulation, whose sex-specific differences may be a reason for the sexual dimorphism of aneuploidy in gametogenesis.
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