Absence of a robust mitotic timer mechanism in early preimplantation mouse embryos leads to chromosome instability

Abstract

Preimplantation embryos often consist of a combination of euploid and aneuploid cells, suggesting that safeguards preventing the generation and propagation of aneuploid cells in somatic cells might be deficient in embryos. In somatic cells, a mitotic timer mechanism has been described, in which even a small increase in the duration of M phase can cause a cell cycle arrest in the subsequent interphase, preventing further propagation of cells that have undergone a potentially hazardously long M phase. Here, we report that cell divisions in the mouse embryo and embryonic development continue even after a mitotic prolongation of several hours. However, similar M-phase extensions caused cohesion fatigue, resulting in prematurely separated sister chromatids and the production of micronuclei. Only extreme prolongation of M phase caused a subsequent interphase arrest, through a mechanism involving DNA damage. Our data suggest that the simultaneous absence of a robust mitotic timer and susceptibility of the embryo to cohesion fatigue could contribute to chromosome instability in mammalian embryos. This article has an associated ‘The people behind the papers’ interview.

Early onset of APC/C activity renders SAC inefficient in mouse embryos

“…In oocytes, the origin of chromosome segregation errors was extensively studied in multiple species, including mice and humans. The problem, at least in mouse, seems to be caused by an inability to respond adequately to the spindle assembly defects, as reported by several laboratories, including our laboratory ( Nagaoka et al, 2011 ; Gui and Homer, 2012 ; Kolano et al, 2012 ; Lane et al, 2012 ; Sebestova et al, 2012 ; Allais and FitzHarris, 2022 ). In human oocytes, chromosome segregation is even more compromised ( Mihajlovic and FitzHarris, 2018 ; Charalambous et al, 2022 ).…”

HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

“…Aneuploidy is a common event during pre-implantation development due to a permissive SAC and replication stress [2][3][4] . Here, we describe different strategies to study how the embryo responds to aneuploidy, activates DNA repair mechanisms, tolerates chromosomal instability, and behaves in a mosaic context.…”

“…The outer cells will differentiate into the trophectoderm (TE), which will give rise to the placenta, while the ICM will give rise to the primitive endoderm (PE) and epiblast (EPI) that sort into distinct layers in the blastocyst 1 . Intriguingly, the first zygotic 2 cleavage-stage divisions in human embryos are error prone, generally resulting in aneuploidy, in which cells gain or lose chromosomes [2][3][4][5][6] .…”

Chromosome Division in Early Embryos—Is Everything under Control? And Is the Cell Size Important?

“…On one hand, embryos are able to quickly achieve microtubule-to-kinetochore connections and establish chromosome congression without defects [131]. On the other hand, they seem to lack a cell-cycle timer and tend to spend longer in mitosis, which in-creases the probability of chromosome missegregation due to the weakening of chromosome cohesion [132]. They also frequently harbor micronuclei resulting from the encapsulation of lagging chromosomes or chromosomal fragments by membranes [100,[133][134][135].…”