Faisal Imrul, Kauppi Liisa
Genome-Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki FI-00290, Finland.
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki FI-00290, Finland.
Development. 2017 Jun 1;144(11):1988-1996. doi: 10.1242/dev.149492. Epub 2017 May 15.
In meiosis, non-exchange homologous chromosomes are at risk for mis-segregation and should be monitored by the spindle assembly checkpoint (SAC) to avoid formation of aneuploid gametes. Sex chromosome mis-segregation is particularly common and can lead to sterility or to aneuploid offspring (e.g. individuals with Turner or Klinefelter syndrome). Despite major implications for health and reproduction, modifiers of meiotic SAC robustness and the subsequent apoptotic response in male mammals remain obscure. Levels of SAC proteins, e.g. MAD2, are crucial for normal checkpoint function in many experimental systems, but surprisingly, apparently not in male meiosis, as indicated by the lack of chromosome segregation defects reported earlier in spermatocytes. To directly test whether MAD2 levels impact the meiotic response to mis-segregating chromosomes, we used βonly mice that are prone to non-exchange X-Y chromosomes. We show that reduced MAD2 levels attenuate the apoptotic response to mis-segregating sex chromosomes and allow the formation of aneuploid sperm. These findings demonstrate that SAC protein levels are crucial for the efficient elimination of aberrant spermatocytes.
在减数分裂过程中，未发生交换的同源染色体有发生错误分离的风险，纺锤体组装检查点（SAC）应对其进行监测，以避免非整倍体配子的形成。性染色体错误分离尤为常见，可导致不育或非整倍体后代（如患有特纳综合征或克兰费尔特综合征的个体）。尽管对健康和生殖有重大影响，但雄性哺乳动物减数分裂SAC稳健性的调节因子以及随后的凋亡反应仍不清楚。在许多实验系统中，SAC蛋白（如MAD2）的水平对于正常的检查点功能至关重要，但令人惊讶的是，在雄性减数分裂中显然并非如此，正如早期在精母细胞中未报道染色体分离缺陷所表明的那样。为了直接测试MAD2水平是否影响对错误分离染色体的减数分裂反应，我们使用了易发生未交换X-Y染色体的β仅小鼠。我们发现，降低MAD2水平会减弱对错误分离性染色体的凋亡反应，并允许形成非整倍体精子。这些发现表明，SAC蛋白水平对于有效消除异常精母细胞至关重要。
