Investigating the consequences of chromosome abnormalities arising during pre-implantation development of the mouse
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University of Cambridge
Department of Physiology, Development and Neuroscience
Department of Physiology, Development and Neuroscience
Abstract
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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.
This work was sponsored by a Wellcome Trust Clinical PhD Fellowship
This work was sponsored by a Wellcome Trust Clinical PhD Fellowship