A versatile cohesion manipulation system probes female reproductive age-related egg aneuploidy

TL;DR

This study creates a system to manipulate chromosome cohesion in mouse eggs, revealing how aging causes chromosome errors and how other factors worsen these errors.

Contribution

A tunable system for cohesion manipulation in live oocytes reveals a threshold for aneuploidy and how age-related defects amplify it.

Findings

Premature sister chromatid separation increases sharply when REC8 levels drop below a critical threshold.

Cytoskeletal and centromere defects worsen aneuploidy in the context of weakened cohesion.

The system enables direct observation of cohesion protein behavior during meiosis.

Abstract

Female reproductive aging is accompanied by a sharp increase in egg aneuploidy rates. Premature loss of chromosome cohesion proteins and early separation of chromosomes are thought to cause high aneuploidy rates during maternal aging. However, because cohesion loss occurs gradually throughout a woman’s reproductive lifespan, and because cytoskeletal defects alone can lead to chromosomal abnormalities, the main causes of the rapid rise in aneuploidy at older reproductive ages are still unclear. In this study, we created a versatile and tunable cohesion manipulation system that enables rapid, dose-dependent degradation of the meiotic cohesin REC8 in live mouse oocytes. By coupling this system with quantitative high-resolution live imaging, we directly observed cohesion protein behavior during meiosis and tested the longstanding threshold model of aneuploidy development. Our results show that premature sister chromatid separation sharply increases only when REC8 levels drop below a critical threshold, supporting the idea of a nonlinear, vulnerability-triggering cohesion limit. We also used our system to examine how other age-related issues, such as cytoskeletal disruption and partial centromere dysfunction, can exacerbate chromatid separation in the context of weakened cohesion. This work provides a tractable oocyte platform for modeling and dissecting the multifactorial mechanisms driving female reproductive age-related egg aneuploidy.

To study pathways that lead to aneuploidy during aging, the authors provide a system that enables cohesion protein depletion in mouse oocytes, mimicking effects that occur during aging. They uncover a threshold for cohesion loss driving chromosome errors and show that actin and centromere defects amplify aneuploidy.

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