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Autophagy-mediated apoptosis eliminates chromosomally abnormal cells from the mouse epiblast

last modified Jun 18, 2020 01:02 PM
New paper in Nature Communications by the Zernicka-Goetz group shows that apoptosis and autophagy ensure aneuploid cells in early stage embryos do not proceed through post-implantation development of the fetus

Images from time-lapse series showing apoptosis of an aneuploid cell during pre- to post-implantation development of a diploid (red)-aneuploid (green) mosaic mouse chimera

 

Whole chromosomal aneuploidies – loss and/or gain of chromosomes from a euploid complement – are responsible for the low fecundity and developmental defects in humans. However, there is a dramatic decline in the prevalence of aneuploidy as gestation progresses. This study by the Zernicka-Goetz lab is out in Nature Communications elucidating the mechanisms by which the abnormal cells are eliminated in a mouse model of aneuploidy. By making time-lapse movies of development in an in vitro culture system, capable of recapitulating implantation and early post-implantation events, we have found that aneuploid cells are eliminated from the mosaic epiblast via programmed cell death. Interestingly, healthy diploid cells from the mosaic epiblast were found to simultaneously undergo over-proliferation to compensate for the loss. In this way, the final size of the embryo remained unchanged from that of the normal embryos. This plasticity provides embryos with potential to develop into healthy babies.

Our study also reveals how aneuploid cells from the mouse epiblast are directed towards apoptosis. These aneuploid cells are found to be are under chronic stress due to the unbalanced production of proteins from the abnormal number of chromosomes. This stress in turn activates a catabolic process, known as autophagy that leads to the death of the abnormal cells in a p53-dependent process.

Together, this work brings us closer to understand the first few days of our lives and gives insight into the reasons behind sub-fertility and the developmental defects and miscarriages that occur during early pregnancy. Future studies in higher mammalian species are however required to reveal if p53-dependent autophagy and apoptosis of the aneuploid cells are conserved mechanisms in mammals.

Reference Singla, S. et al. Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism. Nat. Commun. (2020). https://doi.org/10.1038/s41467-020-16796-3