Susceptibility of mammalian oocytes to chromosome segregation errors with maternal aging

Research Doctorate - Doctor of Philosophy (PhD)Advancing maternal age is a well-established risk factor associated with chromosome segregation errors in oocytes. In this thesis, I employed real-time high resolution imaging to examine the onset of aneuploidy and mechanisms regulating chromosome segregation in mouse oocytes. Specifically I determined 1) that although considerable cohesion loss occurs during MI, bivalent dynamics are not grossly affected, instead premature separation of dyads in MII was found to be the major segregation defect; 2) aged oocytes have decreased levels of SAC proteins on the kinetochores and possess both a lowered ability to maintain SAC arrest and re-establish bivalent biorientation following spindle disruption; 3) a genetic basis to aneuploidy susceptibility is likely to exist as suggested by the distinct aneuploidy phenotypes of two different mouse strains and 4) demonstrated that Ndc80 N-terminal modification was able to impose a robust SAC signalling, in doing so prevent chromosome mis-segregation in young mouse oocytes. Altogether this thesis directly examined the precise timing of chromosome segregation errors, and re-emphasized the role of a weakened SAC in maternal age-related aneuploidy