Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential.

Helen Bolton,Niels Van Der Aa,Magdalena Zernicka-Goetz,Elia Fernandez Gallardo,Sarah J L Graham,Parveen Kumar,Koen Theunis,Thierry Voet

doi:10.1038/ncomms11165

Abstract

Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. By treating embryos with a spindle assembly checkpoint inhibitor during the four- to eight-cell division, we efficiently generate aneuploid cells, resulting in embryo death during peri-implantation development. Live-embryo imaging and single-cell tracking in chimeric embryos, containing aneuploid and euploid cells, reveal that the fate of aneuploid cells depends on lineage: aneuploid cells in the fetal lineage are eliminated by apoptosis, whereas those in the placental lineage show severe proliferative defects. Overall, the proportion of aneuploid cells is progressively depleted from the blastocyst stage onwards. Finally, we show that mosaic embryos have full developmental potential, provided they contain sufficient euploid cells, a finding of significance for the assessment of embryo vitality in the clinic.

Highlights

Most human pre-implantation embryos are mosaics of euploid and aneuploid cells
Mouse pre-implantation development is similar to that in humans, undergoing cleavage divisions, compaction, blastocyst cavity formation and hatching, albeit with slightly different timings[10,11,12]. Both mouse and human pre-implantation development culminates in the formation of a blastocyst that is composed of the extra-embryonic trophectoderm (TE) and primitive endoderm (PE), which will form the placenta and yolk sac, respectively, and the embryonic epiblast (EPI), which forms the fetus[12,13]
By determining the development of mosaic embryos at single-cell resolution, we show that aneuploid cells become eliminated from the embryo, starting just before implantation, and that mosaic euploid–aneuploid embryos have comparable developmental potential to normal embryos, provided they contain a sufficient proportion of euploid cells

Summary

Introduction

Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. 3 Sanger Institute-EBI Single-Cell Genomics Centre, Wellcome he majority of human pre-implantation embryos display chromosome mosaicism, with the most common pattern being euploid–aneuploid mosaicism where the embryo contains a complement of both normal and abnormal cells[1]. Both mouse and human pre-implantation development culminates in the formation of a blastocyst that is composed of the extra-embryonic trophectoderm (TE) and primitive endoderm (PE), which will form the placenta and yolk sac, respectively, and the embryonic epiblast (EPI), which forms the fetus[12,13] These cell lineages are specified in two cell fate decisions. By determining the development of mosaic embryos at single-cell resolution, we show that aneuploid cells become eliminated from the embryo, starting just before implantation, and that mosaic euploid–aneuploid embryos have comparable developmental potential to normal embryos, provided they contain a sufficient proportion of euploid cells

Methods

Results

Conclusion