Tetraploidy causes chromosomal instability in acentriolar mouse embryos

Abstract

Tetraploidisation is considered a common event in the evolution of chromosomal instability (CIN) in cancer cells. The current model for how tetraploidy drives CIN in mammalian cells is that a doubling of the number of centrioles that accompany the genome doubling event leads to multipolar spindle formation and chromosome segregation errors. By exploiting the unusual scenario of mouse blastomeres, which lack centrioles until the ~64-cell stage, we show that tetraploidy can drive CIN by an entirely distinct mechanism. Tetraploid blastomeres assemble bipolar spindles dictated by microtubule organising centres, and multipolar spindles are rare. Rather, kinetochore-microtubule turnover is altered, leading to microtubule attachment defects and anaphase chromosome segregation errors. The resulting blastomeres become chromosomally unstable and exhibit a dramatic increase in whole chromosome aneuploidies. Our results thus reveal an unexpected mechanism by which tetraploidy drives CIN, in which the acquisition of chromosomally-unstable microtubule dynamics contributes to chromosome segregation errors following tetraploidisation.

Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis

“… 8 In some cases after failed cytokinesis, this may give rise to binucleate cells 3 . Tetraploidy is observed in human conceptuses, however, it also induces chromosomal instability, aneuploidy, and tumorogenesis in mouse embryos 9,10 . Other mechanisms including those associated with embryonic arrest have been reviewed by Daughtry and Chavez 11 …”

Chromosome dynamics and spindle microtubule establishment in mouse embryos

“…Aurora kinases may function in embryos to keep MT attachments unstable, as opposed to correcting stable merotelic attachments. Moreover, the error correction pathway may be more important in suboptimal conditions, or when chromosome segregation mechanisms are otherwise hampered or challenged 34 . Our data thus form a framework for future studies of segregation error and aneuploidy genesis in this unusual and clinically relevant system.…”

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

“…provides a readout of KT-MT turnover that is necessary for error correction, whereas a fast turnover component (T1/2 in sec.) indicates non-stabilised spindle MTs (Bakhoum et al, 2009a; Cimini et al, 2006; Paim and FitzHarris, 2019; Zhai et al, 1995). Mathematical deconvolution of these two components reveals the relative sizes of the two MT populations (Fig.…”

“…Next, we sought an entirely different approach to decrease the incidence of lagging chromosomes. In mitotic cells, depletion of mitotic centromere-associated kinesin (MCAK) increases production of lagging chromosomes (Ganem et al, 2005; Kline-Smith et al, 2004; Maney et al, 1998) while its overexpression can reduce the likelihood of lagging (Bakhoum et al, 2009b; Kabeche and Compton, 2012; Paim and FitzHarris, 2019; Wordeman et al, 2007). In oocytes, MCAK transcript levels decrease with maternal age (Pan et al, 2008), causing us to hypothesize that it may underlie age-related anaphase lagging.…”