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.

Mosaicism in Preimplantation Human Embryos: When Chromosomal Abnormalities Are the Norm

“…These observations are consistent with a second model of clonal depletion (Figure 4), whereby aneuploid cells are actively eliminated or fail to propagate effectively within mosaic embryos, mitigating their deleterious impact. A recent study using a mouse model provides empirical support for this hypothesis, demonstrating that mosaic embryos can be rescued by diploid cells if present in sufficient frequency (≥50%) [84]. This experiment also revealed that the fate of aneuploid cells depends on the type of cell affected.…”

“…This experiment also revealed that the fate of aneuploid cells depends on the type of cell affected. Aneuploidies occurring in the blastocyst were better tolerated—though still deleterious—when isolated to the extraembryonic TE tissue [84]. Mitotic errors affecting the inner cell mass of mouse embryos were more consequential and eliminated by apoptosis prior to implantation [84].…”

“…Aneuploidies occurring in the blastocyst were better tolerated—though still deleterious—when isolated to the extraembryonic TE tissue [84]. Mitotic errors affecting the inner cell mass of mouse embryos were more consequential and eliminated by apoptosis prior to implantation [84]. While enlightening, the conclusions derived from mouse studies should not be assumed to apply directly to humans, as 80% of mouse embryos form blastocysts in vitro compared to only 30–50% of human embryos [85].…”

Assessment of pre‐implantation genetic testing for embryo aneuploidies: A SWOT analysis

“…Recent studies showed that mosaic blastocysts miscarry more often and implant less frequently than an euploid blastocyst but a proportion of mosaic embryos can implant and result in healthy babies . In a chimeric murine model, mosaic embryos have been shown to undergo a “self‐correcting” mechanism if they contain sufficient euploid cells …”

Technology versus biology: the limits of pre‐implantation genetic screening

“…Moreover, some mosaic embryos—which are usually not implanted—can still grow into healthy newborns . Indeed, recent murine studies suggest that mosaic embryos with a significant complement of euploid cells retain full developmental potential . Mosaicism can go undiagnosed because a single TE biopsy is not representative of the karyotypically heterogeneous monolayer or of the ICM.…”