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Yale University

Nature Aging, Published: 03 November 2025 | https://doi.org/10.1038/s43587-025-00997-w A versatile cohesion manipulation system probes female reproductive age-related egg aneuploidy

Jiyeon Leem¹, Tom Lemonnier¹, Ani Khutsaidze¹, Lei Tian², Xiaojun Xing², Suxia Bai³, Timothy Nottoli³ & Binyam Mogessie^1,4

¹Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
²Yale Genome Editing Center, Yale University School of Medicine, New Haven, CT, USA.
³Department of Comparative Medicine, Yale Genome Editing Center, Yale University School of Medicine, New Haven, CT, USA.
⁴Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.

Corresponding author
Correspondence to Binyam Mogessie.

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.

논문정보

형식Research article
게재일2025년 11월 (BRIC 등록일 2025-11-04)
연구진국외 연구진
분야 생명과학 > 발생생물학

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