Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism

Shruti Singla,Meng Zhu,Lisa K Iwamoto-Stohl,Magdalena Zernicka-Goetz

doi:10.1038/s41467-020-16796-3

Shruti Singla, Meng Zhu + Show 2 more

Open Access

https://doi.org/10.1038/s41467-020-16796-3

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Abstract

The high incidence of aneuploidy in the embryo is considered the principal cause for low human fecundity. However, the prevalence of aneuploidy dramatically declines as pregnancy progresses, with the steepest drop occurring as the embryo completes implantation. Despite the fact that the plasticity of the embryo in dealing with aneuploidy is fundamental to normal development, the mechanisms responsible for eliminating aneuploid cells are unclear. Here, using a mouse model of chromosome mosaicism, we show that aneuploid cells are preferentially eliminated from the embryonic lineage in a p53-dependent process involving both autophagy and apoptosis before, during and after implantation. Moreover, we show that diploid cells in mosaic embryos undertake compensatory proliferation during the implantation stages to confer embryonic viability. Together, our results indicate a close link between aneuploidy, autophagy, and apoptosis to refine the embryonic cell population and ensure only chromosomally fit cells proceed through development of the fetus.

Highlights

The high incidence of aneuploidy in the embryo is considered the principal cause for low human fecundity
We treated non-fluorescent embryos with reversine at the four- to eight-cell stage division and membranetargeted red fluorescent embryos with DMSO, let embryo develop to the eight-cell stage at which point we isolated individual cells from each other and aggregated four red fluorescent diploid and four non-fluorescent aneuploid cells into the chimeras, and let them develop to the blastocyst stage (Fig. 1a)
In this study, we have made three principle discoveries: first, that aneuploid cells are preferentially eliminated by apoptosis during epiblast remodelling at the peri- and early post-implantation stages of development and prior to gastrulation; second, that p53-induced autophagy is required to eliminate aneuploid cells and third, that normal diploid cells increase their proliferation rate to compensate for aneuploid cell elimination to regulate embryo size

Summary

Introduction

The high incidence of aneuploidy in the embryo is considered the principal cause for low human fecundity. The incidence of aneuploidy declines at later stages of development, from 73% in pre-implantation stages to only 0.6% in live births[5,8] This reduced frequency of aneuploid cells during embryonic development could arise via the preferential allocation of abnormal cells to extra-embryonic lineages[9,10], the selfcorrection of abnormalities[11] or clonal depletion[12,13]. We recently established a mouse model of chromosome mosaicism[14] by acutely inhibiting the spindle assembly checkpoint (SAC)[15] This model allowed us to discover that aneuploid cells induce different responses in different lineages as the diploid–aneuploid mosaic embryo develops into the blastocyst[14]: apoptosis in the inner cell mass (ICM), which will generate the embryonic lineage and cell cycle delay in the trophectoderm (TE), which will form the placenta. The results we present here demonstrate that aneuploid cells are eliminated from the embryonic lineage by apoptosis, due to proteotoxic stress which in turn activates autophagy, favouring survival of a diploid embryonic cell pool

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