Molecular mechanisms of meiotic segregation errors during female reproductive ageing

Abstract

In humans, the frequency of meiotic segregation errors increases dramatically during female ageing. The impact of this on human reproductive health is amplified by the growing trend for women to postpone childbearing. It has long been known that the majority of meiotic segregation errors occur during the first meiotic division (MI). MI is a unique cell division involving dissolution of bivalent chromosomes formed when maternal and paternal homologs undergo reciprocal exchange of DNA and remain physically linked at chiasmata at the sites of crossover formation. Dissolution of bivalents results in dyad chromosomes consisting of two chromatids linked by centromeric cohesion. Dyads are either lost to the polar body or remain in the oocyte and realign on the metaphase II spindle, where they remain until fertilisation. My work is part of a collaborative project focussed on elucidating the molecular link between female age and chromosome segregation errors during MI. Using an aged mouse model to monitor oocyte chromosome segregation we discovered a dramatically increased incidence of anaphase defects during MI in oocytes from aged mice. This was preceded by depletion of chromosomal cohesin, which is required for cohesion between sister chromatids, thereby stabilising bivalent chromosomes. Consistent with this, single chiasmate bivalents become destabilised during female ageing. Depletion of cohesin was also associated with loss of the unified structure of sister centromeres, which is required for accurate segregation during MI. In addition, cohesin loss was associated with reduced recruitment of its protector, Sgo2. On the basis of these data, I propose that a gradual decline in chromosomal cohesin during female ageing impedes recruitment of Sgo2, which in turn may further amplify cohesin loss during prometaphase resulting in depletion of cohesin below the threshold required to maintain bivalent architecture. According to this hypothesis, cohesin depletion is sufficient to explain the age-related increase in MI errors and provides a plausible molecular mechanism for the association between female age and germ cell genomic instability.

I