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

TLDR

Human pre‑implantation embryos are typically mosaics of euploid and aneuploid cells. The study aims to determine the fate of aneuploid cells and the developmental potential of mosaic embryos. A mouse model of chromosome mosaicism was created by treating embryos with a spindle‑assembly‑checkpoint inhibitor during the four‑to‑eight‑cell stage, producing aneuploid cells that cause peri‑implantation death. Live‑embryo imaging shows that aneuploid cells are lineage‑specific: they are eliminated by apoptosis in the fetal lineage but exhibit proliferative defects in the placental lineage, their proportion declines from the blastocyst stage onward, yet mosaic embryos retain full developmental potential when euploid cells are sufficient.

Abstract

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.