Dong Jie, Jin Liping, Bao Shihua, Chen Biaobang, Zeng Yang, Luo Yuxi, Du Xingzhu, Sang Qing, Wu Tianyu, Wang Lei
Institute of Pediatrics, Children's Hospital of Fudan University and Institutes of Biomedical Sciences, The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Cell Discov. 2023 Oct 24;9(1):105. doi: 10.1038/s41421-023-00599-z.
Aneuploidy seriously compromises female fertility and increases incidence of birth defects. Rates of aneuploidy in human eggs from even young women are significantly higher than those in other mammals. However, intrinsic genetic factors underlying this high incidence of aneuploidy in human eggs remain largely unknown. Here, we found that ectopic expression of human TUBB8 in mouse oocytes increases rates of aneuploidy by causing kinetochore-microtubule (K-MT) attachment defects. Stretched bivalents in mouse oocytes expressing TUBB8 are under less tension, resulting in continuous phosphorylation status of HEC1 by AURKB/C at late metaphase I that impairs the established correct K-MT attachments. This reduced tension in stretched bivalents likely correlates with decreased recruitment of KIF11 on meiotic spindles. We also found that ectopic expression of TUBB8 without its C-terminal tail decreases aneuploidy rates by reducing erroneous K-MT attachments. Importantly, variants in the C-terminal tail of TUBB8 were identified in patients with recurrent miscarriages. Ectopic expression of an identified TUBB8 variant in mouse oocytes also compromises K-MT attachments and increases aneuploidy rates. In conclusion, our study provides novel understanding for physiological mechanisms of aneuploidy in human eggs as well as for pathophysiological mechanisms involved in recurrent miscarriages.
非整倍体严重损害女性生育能力，并增加出生缺陷的发生率。即使是年轻女性的人类卵子中的非整倍体率也显著高于其他哺乳动物。然而，人类卵子中非整倍体高发生率背后的内在遗传因素在很大程度上仍不清楚。在这里，我们发现人类TUBB8在小鼠卵母细胞中的异位表达通过导致动粒-微管（K-MT）附着缺陷而增加非整倍体率。表达TUBB8的小鼠卵母细胞中伸展的二价体张力较小，导致减数分裂中期I后期AURKB/C对HEC1的持续磷酸化状态，从而损害已建立的正确K-MT附着。伸展二价体中这种降低的张力可能与减数分裂纺锤体上KIF11募集减少有关。我们还发现，没有C末端尾巴的TUBB8异位表达通过减少错误的K-MT附着而降低非整倍体率。重要的是，在反复流产患者中鉴定出了TUBB8 C末端尾巴的变体。在小鼠卵母细胞中鉴定出的TUBB8变体的异位表达也会损害K-MT附着并增加非整倍体率。总之，我们的研究为人类卵子中非整倍体的生理机制以及反复流产所涉及的病理生理机制提供了新的认识。
