Distinct classes of lagging chromosome underpin age-related oocyte aneuploidy in mouse

• Published in: Developmental cell Vol. 56; no. 16; pp. 2273 - 2283.e3
• Main Authors: Mihajlović, Aleksandar I., Haverfield, Jenna, FitzHarris, Greg
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 23-08-2021
• Subjects: aging; APCin; chromosome segregation errors; fertility; kinetochore; lagging chromosomes; M-phase extension; MCAK; meiosis I; microtubule; oocyte; meiosis I; APCin; microtubule; oocyte; MCAK; M-phase extension; fertility; kinetochore; aging; lagging chromosomes; chromosome segregation errors
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2021.07.022

Chromosome segregation errors that cause oocyte aneuploidy increase in frequency with maternal age and are considered a major contributing factor of age-related fertility decline in females. Lagging anaphase chromosomes are a common age-associated phenomenon in oocytes, but whether anaphase laggards actually missegregate and cause aneuploidy is unclear. Here, we show that lagging chromosomes in mouse oocytes comprise two mechanistically distinct classes of chromosome motion that we refer to as “class-I” and “class-II” laggards. We use imaging approaches and mechanistic interventions to dissociate the two classes and find that whereas class-II laggards are largely benign, class-I laggards frequently directly lead to aneuploidy. Most notably, a controlled prolongation of meiosis I specifically lessens class-I lagging to prevent aneuploidy. Our data thus reveal lagging chromosomes to be a cause of age-related aneuploidy in mouse oocytes and suggest that manipulating the cell cycle could increase the yield of useful oocytes in some contexts.
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•Lagging chromosomes comprise two distinct movement types with differential outcomes•Class-I lagging chromosomes contribute to aneuploidy, class-II do not•M-phase prolongation limits class-I lagging and age-related aneuploidy in oocytes•MCAK overexpression limits class-II lagging but has no impact on aneuploidy
Mihajlović et al. reveal the existence of two distinct classes of lagging anaphase chromosomes in oocytes with differing implications for aneuploidy. Experimental prolongation of M-phase limits class-I lagging and consequently prevents aneuploidy that is associated with advanced maternal age.