Ectopic expression of human TUBB8 leads to increased aneuploidy in mouse oocytes

Jie Dong; Liping Jin; Shihua Bao; Biaobang Chen; Yang Zeng; Yuxi Luo; Xingzhu Du; Qing Sang; Tianyu Wu; Lei Wang

doi:10.1038/s41421-023-00599-z

Ectopic expression of human TUBB8 leads to increased aneuploidy in mouse oocytes

Cell Discov. 2023 Oct 24;9(1):105. doi: 10.1038/s41421-023-00599-z.

Authors

Jie Dong^#¹, Liping Jin^#², Shihua Bao^#³, Biaobang Chen⁴, Yang Zeng¹, Yuxi Luo¹, Xingzhu Du¹, Qing Sang⁵, Tianyu Wu⁶, Lei Wang⁷

Affiliations

¹ 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.
² 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.
³ Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
⁴ NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China.
⁵ 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. sangqing@fudan.edu.cn.
⁶ 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. ty_wu@fudan.edu.cn.
⁷ 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. wangleiwanglei@fudan.edu.cn.

^# Contributed equally.

Abstract

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.

Abstract

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