Intrinsically Defective Microtubule Dynamics Contribute to Age-Related Chromosome Segregation Errors in Mouse Oocyte Meiosis-I

Abstract

Chromosome segregation errors in mammalian oocytes compromise development and are particularly prevalent in older females, but the aging-related cellular changes that promote segregation errors remain unclear [1, 2]. Aging causes a loss of meiotic chromosome cohesion, which can explain premature disjunction of sister chromatids [3-7], but why intact sister pairs should missegregate in meiosis-I (termed non-disjunction) remains unknown. Here, we show that oocytes from naturally aged mice exhibit substantially altered spindle microtubule dynamics, resulting in transiently multipolar spindles that predispose the oocytes to kinetochore-microtubule attachment defects and missegregation of intact sister chromatid pairs. Using classical micromanipulation approaches, including reciprocally transferring nuclei between young and aged oocytes, we show that altered microtubule dynamics are not attributable to age-related chromatin changes. We therefore report that altered microtubule dynamics is a novel primary lesion contributing to age-related oocyte segregation errors. We propose that, whereas cohesion loss can explain premature sister separation, classical non-disjunction is instead explained by altered microtubule dynamics, leading to aberrant spindle assembly.