Abstract
Female meiosis is a specialised form of cell division responsible for the creation of a haploid egg containing 23 chromosomes. Of concern, ageing is accompanied by aneuploidy (incorrect chromosome numbers) in mammalian eggs, an underlying factor for an increased incidence of pregnancy failures seen in reproductively older females. This is consistent with an age-related decline in centromeric cohesion proteins leading to premature separation of sister chromatids during meiosis. Such a progressive loss of cohesion cannot however explain a sharp rise in aneuploidy recorded in older female eggs. Recent studies have highlighted an emerging role for the actin cytoskeleton in ensuring faithful segregation during meiosis. Here, the relationship between cohesion and actin is explored in reproductively young and aged eggs.In this work F-actin is shown to help keep most sister chromatids together after centromeric cohesion has been lost in aged eggs. F-actin disruption caused premature separation in young eggs, whilst further exacerbating separation in aged eggs. Interestingly, F-actin loss did not affect canonical cohesion complexes, suggesting that F-actin disruption no longer limits spindle-microtubule pulling forces. Furthermore, experimentally reducing cohesion caused accelerated separation when F-actin was disrupted. Conversely, enriching F-actin within the meiotic spindle when cohesion complexes had been fully degraded, significantly reduced premature separation, suggesting that microtubule pulling forces are limited by F-actin. Finally, quantitative super-resolution microscopy revealed a spindle-specific decline in F-actin in aged eggs, stipulating its importance in preventing aneuploidy. These findings suggest that: actin limits premature sister chromatid separation, which would normally arise from centromeric cohesion decline, by limiting microtubule-based pulling forces and that loss of spindle F-actin may underlie the exponential increase in aneuploidy recorded in aged eggs.
| Date of Award | 21 Mar 2023 |
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| Original language | English |
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| Supervisor | Binyam Mogessie (Supervisor) & Mark P Dodding (Supervisor) |