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

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.

Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos

“…From blastocyst stage on aneuploid cells progressively deplete, and mosaic embryos have full developmental potential as long as they contain sufficient euploid cells [18]. With aneuploid cells preferably seggregating into the trophectoderm, it appears reasonable to assume that mosaicism rates will increase with number of trophectoderm biopsies performed.…”

Mosaicism between trophectoderm and inner cell mass

“…Consistent with this finding, a recent study by Bolton and colleagues concluded that there was no evidence for preferential allocation of aneuploid cells in mosaic mouse embryo models (51). To investigate both aneuploid cells' fate and the developmental potential of mosaic embryos, Bolton and colleagues generated a mouse model with euploid-aneuploid chromosome mosaicism using the drug Reversine to inhibit SAC protein monopolar spindle 1-like 1 (Mps1) kinase during the 4-to 8-cell stage transition.…”

Human embryo mosaicism: did we drop the ball on chromosomal testing?

“…Mosaicism is postulated to originate from improper expression of cell cycle checkpoint genes during the primary mitotic cell divisions in the early embryo when maternal transcripts control the cell cycle [9]. At later cleavage stages, the embryonic genome takes over and may be able to overcome mosaicism by allowing the proliferation of normal cells and the inhibition of mitotic activity in abnormal ones [11][12][13]. Such a process is supported by data showing that chromosomal mosaicism is far lower at the blastocyst stage (days 5-6) as compared to the cleavage stage (day 3).…”