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Investigating the consequences of chromosome abnormalities arising during pre-implantation development of the mouse



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Bolton, Helen Louise 


The majority of human pre-implantation embryos created through in vitro fertilization (IVF) are mosaic as they are constituted of a mixture of diploid and aneuploid cells. Chromosome abnormalities are widely believed to contribute towards the relatively low success rates of IVF treatment. Consequently major efforts have been undertaken to develop effective tools to aid the selection of embryos with minimal abnormalities with the aim of improving clinical outcomes. However, the ultimate fate of mosaic embryos is not known. Human embryo research is limited by practical and ethical constraints, and directly relevant animal studies are sparse. To circumvent many of these limitations, a mouse model for pre-implantation chromosome mosaicism was developed. Acute chromosome segregation errors were induced in cleavage stage mouse blastomeres by bypassing the spindle assembly checkpoint (SAC). This model was used to investigate the fate of abnormal cells within the developing pre-implantation embryo, and the ultimate developmental outcome of mosaic embryos. Time-lapse imaging of pre-implantation development revealed that cells with chromosome abnormalities were progressively depleted during blastocyst maturation; inner cell mass (ICM) cells exhibited higher rates of apoptosis, while in the trophectoderm (TE) lineage effects on the cell-cycle predominated. Depletion continued throughout post-implantation development. Significantly, the presence of a critical number of control blastomeres within the embryo could rescue the early post-implantation lethality that occurred in embryos containing high rates of abnormalities. Thus it was demonstrated that mosaic embryos can achieve full developmental potential and that abnormal cells are progressively depleted as development proceeds. Finally, the mechanisms responsible for eliminating the abnormal cells from the embryo were investigated, revealing that embryos containing chromosome abnormalities may have increased metabolic requirements which could contribute to their clonal depletion; a feature previously characterised in aneuploid cells in the context of cancer research.






Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
This work was sponsored by a Wellcome Trust Clinical PhD Fellowship