Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II

Ibtissem Nabti,John Carroll,Petros Marangos,Rosanna Grimes,Hema Sarna

doi:10.1038/ncomms15346

Abstract

Sister chromatid attachment during meiosis II (MII) is maintained by securin-mediated inhibition of separase. In maternal ageing, oocytes show increased inter-sister kinetochore distance and premature sister chromatid separation (PSCS), suggesting aberrant separase activity. Here, we find that MII oocytes from aged mice have less securin than oocytes from young mice and that this reduction is mediated by increased destruction by the anaphase promoting complex/cyclosome (APC/C) during meiosis I (MI) exit. Inhibition of the spindle assembly checkpoint (SAC) kinase, Mps1, during MI exit in young oocytes replicates this phenotype. Further, over-expression of securin or Mps1 protects against the age-related increase in inter-sister kinetochore distance and PSCS. These findings show that maternal ageing compromises the oocyte SAC–APC/C axis leading to a decrease in securin that ultimately causes sister chromatid cohesion loss. Manipulating this axis and/or increasing securin may provide novel therapeutic approaches to alleviating the risk of oocyte aneuploidy in maternal ageing.

Highlights

Sister chromatid attachment during meiosis II (MII) is maintained by securin-mediated inhibition of separase
Maintaining tight control of securin during the MI-to-MII transition is essential to ensure sufficient securin remains in MII so as to inhibit separase and maintain sister chromatid cohesion until fertilization triggers exit from MII19
Because strain differences have been reported in the susceptibility of oocyte quality to aging[25], we first set out to determine if MII eggs from our laboratory-aged MF1 mice exhibit age-related changes reported in other laboratories

Summary

Introduction

Sister chromatid attachment during meiosis II (MII) is maintained by securin-mediated inhibition of separase. Over-expression of securin or Mps[1] protects against the age-related increase in inter-sister kinetochore distance and PSCS These findings show that maternal ageing compromises the oocyte SAC–APC/C axis leading to a decrease in securin that causes sister chromatid cohesion loss. This selective cleavage of cohesin on chromosome arms is achieved through a Shugoshin (Sgo2)-mediated protection of centromeric cohesion[9,15,16,17,18] Loss of this protection, or overriding it through unbridled separase activity leads to premature sister chromatid separation in MI due to premature cleavage of centromeric cohesin[9,15,16,17,18]. Maintaining tight control of securin during the MI-to-MII transition is essential to ensure sufficient securin remains in MII so as to inhibit separase and maintain sister chromatid cohesion until fertilization triggers exit from MII19

Methods

Results

Conclusion