Insufficiency of cohesin regulatory protein PDS5B triggers meiotic failure and aneuploidy in oocytes during advanced maternal aging.

Abstract

Oocytes rely on a cohort of proteins whose sustained expression ensures normal meiotic progression and reproductive competence throughout an animal's reproductive life. Age-related declines in these proteins are a major cause of reduced oocyte quality and female fertility during reproductive aging. Here, we report that the cohesin regulatory protein PDS5B, a dynamically maintained factor in oocytes, declines with age and plays a noncanonical role in the spindle pole formation independent of its cohesion function during oocyte meiotic maturation. Specifically, we found that PDS5B was expressed throughout the oocyte meiosis and localized at the spindle poles at metaphase stages, while its protein abundance was reduced in aged oocytes, concomitant with decreased messenger ribonucleic acid (mRNA) levels and translational efficiency. Knockdown or heterozygous knockout of PDS5B caused spindle assembly defects, meiotic arrest, and aneuploidy in oocytes, ultimately leading to female subfertility. Mechanistically, immunoprecipitation/mass spectrometry analyses revealed that PDS5B recruited deubiquitinating enzyme USP9X to spindle poles to stabilize nuclear mitotic apparatus and promote proper spindle assembly. Moreover, expression of exogenous PDS5B in aged oocytes partially alleviated meiotic defects associated with advanced maternal age. Altogether, our findings uncover a unique spindle pole-specific function of PDS5B in oocytes and suggest that maintaining PDS5B levels may be a potential strategy to improve the quality of aged oocytes.