Reduced Chromosome Cohesion Measured by Interkinetochore Distance Is Associated with Aneuploidy Even in Oocytes from Young Mice1

Abstract

It is becoming clear that reduced chromosome cohesion is an important factor in the rise of maternal age-related aneuploidy. This reduction in cohesion has been observed both in human and mouse oocytes, and it can be measured directly by an increase with respect to maternal age in interkinetochore (iKT) distance between a sister chromatid pair. We have observed variations in iKT distance even in oocytes from young mice and wondered if such differences may predispose those oocytes displaying the greatest iKT distances to be becoming aneuploid. Therefore, we used two methods, one pharmacological (Aurora kinase inhibitor) and one genetic (Fzr1 knockout), to raise aneuploidy rates in oocytes from young mice (age, 1-3 mo) and to examine if those oocytes that were aneuploid had greater iKT distances. We observed that for both Aurora kinase inhibition and Fzr1 knockout, iKT distances were significantly greater in those oocytes that became aneuploid compared to those that remained euploid. Based on these results, we propose that individual oocytes undergo loss in chromosomal cohesion at different rates and that the greater this loss, the greater the risk for becoming aneuploid.

Kinetochore microtubule establishment is defective in oocytes from aged mice

“…In somatic (mitotic) cells merotelic attachments are hazardous, as they go unnoticed by the spindle assembly checkpoint, but can lead to aneuploidy. 7,9 Consistent with a role for equivalent meiotic-merotelic attachments in meiosis-I aneuploidy, lagging chromosomes are common in oocytes from old mothers; 13,14 treatments that might promote meiotic-merotelic attachments can promote aneuploidy in oocytes, 30,31 and misattachments have been directly observed in meiosis-I in young mice. 22,32 Here we find that meiotic-merotelic attachments are relatively Analysis of the microtubule attachment-type data presented in Figure 3, categorized according to kinetochore morphology.…”

Molecular causes of aneuploidy in mammalian eggs

“…Importantly, an increased distance correlates with those mouse oocytes that are aneuploid in maternal aging studies (Merriman et al, 2012); even in young mice where aneuploidy rates are much lower, those oocytes that are aneuploid tend to have higher distances (Merriman et al, 2013). It is feasible that small changes in the proximity of the two sister kinetochores that constitute a functional unit within each homologue of a bivalent have a dramatic consequence on the efficiency of that pair to establish an attachment to just one pole.…”

Insights into Mechanisms Causing the Maternal Age-Induced Decrease in Oocyte Quality

“…Supporting evidence from aged mice shows that increased iKT distance is positively correlated with age [ 64 , 66 ]. Additionally, absolute iKT distance in all oocytes from aged mice was on average similar to iKT distance in aneuploid oocytes at all other ages [ 66 ], predisposing oocytes to erroneous segregation events and aneuploidy. Furthermore, the signifi cant increase in aneuploidy of oocytes with increased iKT distance suggests some mechanism of cohesion protein loss is leading to aneuploidy.…”