Actin limits egg aneuploidies associated with female reproductive aging

Abstract

Aging-related centromeric cohesion loss underlies premature separation of sister chromatids and egg aneuploidy in reproductively older females. Here, we show that F-actin maintains chromatid association after cohesion deterioration in aged eggs. F-actin disruption in aged mouse eggs exacerbated untimely dissociation of sister chromatids, while its removal in young eggs induced extensive chromatid separation events generally only seen in advanced reproductive ages. In young eggs containing experimentally reduced cohesion, F-actin removal accelerated premature splitting and scattering of sister chromatids in a microtubule dynamics–dependent manner, suggesting that actin counteracts chromatid-pulling spindle forces. Consistently, F-actin stabilization restricted scattering of unpaired chromatids generated by complete degradation of centromeric cohesion proteins. We conclude that actin mitigates egg aneuploidies arising from age-related cohesion depletion by limiting microtubule-driven separation and dispersion of sister chromatids. This is supported by our finding that spindle-associated F-actin structures are disrupted in eggs of reproductively older females.

Epigallocatechin‐3‐gallate improves the quality of maternally aged oocytes

“…Aged oocytes exhibit a disturbance in spindle F‐actin, which in turn exacerbates the premature separation of sister chromatids and leads to egg aneuploidy 42 . Notably, as illustrated by the upregulation of the actin cytoskeleton regulatory gene in aged oocytes following EGCG treatment (Figure 4E), we embarked on investigating its potential role in regulating F‐actin.…”

“…Aged oocytes exhibit a disturbance in spindle F‐actin, which in turn exacerbates the premature separation of sister chromatids and leads to egg aneuploidy. 42 Notably, as illustrated by the upregulation of the actin cytoskeleton regulatory gene in aged oocytes following EGCG treatment (Figure 4E ), we embarked on investigating its potential role in regulating F‐actin. Intriguingly, the application of EGCG indeed led to a substantial enhancement in the expression of F‐actin, especially around the spindle region (Figure 5C ,G–I), underscoring the potential of EGCG to mitigate oocyte aneuploidy, at least in part, through the regulation of F‐actin.…”

“…Notably, the incidence of aneuploidy in human eggs rises with maternal age, surpassing 50% in eggs from women aged 35 years 55,56 . A recent investigation has implicated the disruption of spindle‐associated F‐actin as a pivotal factor in female reproductive ageing, exacerbating the occurrence of aneuploidy 42 . Indeed, actin plays multifaceted roles during meiosis 57 .…”

“…For instance, it orchestrates accurate alignment and segregation of chromosomes, 58 regulates microtubule‐coordinated spindle localisation 59 and facilitates the long‐range transportation of vesicles in mouse oocytes 60 . With advancing reproductive age, the depletion of cohesive proteins and the disruption of spindle‐associated F‐actin collectively diminish spindle actin‐mediated resistance to microtubule‐induced tension, culminating in premature separation of sister chromatids and subsequent aneuploidy 42 …”

“… 55 , 56 A recent investigation has implicated the disruption of spindle‐associated F‐actin as a pivotal factor in female reproductive ageing, exacerbating the occurrence of aneuploidy. 42 Indeed, actin plays multifaceted roles during meiosis. 57 For instance, it orchestrates accurate alignment and segregation of chromosomes, 58 regulates microtubule‐coordinated spindle localisation 59 and facilitates the long‐range transportation of vesicles in mouse oocytes.…”