Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice (#32)

Yan Yun 1 , Janet Holt 1 , Eileen McLaughlin 1 , Keith Jones 1 2
  1. University of Newcastle, Callaghan, NSW, Australia
  2. University of Southampton, Southampton, UK

Mammalian oocytes are susceptible to chromosome mis-segregation, and maternal age is a risk factor. Currently, maternal aging in women, based on mouse models, is thought to raise oocyte aneuploidy rates because chromosome cohesion deteriorates during prophase arrest and Sgo2, a protector of centromeric cohesion, is lost. However, our present study show that the most common mouse strain, C57Bl6/J, is resistant to maternal aging, showing relatively little increase in aneuploidy (1.3% in young mice vs. 9.4% in old mice; p=0.08) or centromeric Sgo2 loss (1561 ± 653 arbitrary intensity in young mice vs. 1623 ± 951 in old mice; p=0.76). Instead it demonstrates significant kinetochore-associated loss in the spindle assembly checkpoint protein Mad2 (1004 ± 422 arbitrary intensity in young oocytes vs. 718 ± 323 in old oocytes; p<0.0001) and phosphorylated Aurora C (1208 ± 600 in young oocytes vs. 609 ± 350 in old oocytes; p<0.0001), which is involved in microtubule-kinetochore error correction. In an unperturbed meiosis I (MI) division such loss appeared to have little impact, but did correlate with a lowered ability of aged oocytes to maintain arrest with nocodazole (25% of young vs. 44.4% of old oocytes undergoing polar body extrusion; p=0.0114). Furthermore, live cell imaging demonstrated that aged oocytes were far less able to establish bivalent biorientation and subsequently produced higher aneuploidy rates in the resulting metaphase II eggs following spindle disruption in MI (10.3% in young vs. 34.5% in old; p=0.0075). These findings have an impact clinically regarding the handling of human oocytes ex vivo during assisted reproductive techniques and suggest there is a genetic basis to aneuploidy susceptibility.