ABSTRACT

More than any other species, humans have difficulty reproducing. As recent studies show that human infertility is ever increasing, much efforts are needed towards the understanding of our low fecundity. While aneuploidy is the leading cause of spontaneous pregnancy loss in humans, we still know surprisingly little about the developmental consequences of chromosomal abnormalities. We have here used a mouse model that spontaneously incites chromosomal primary aneuploidy in female haploid oocytes and find that after fertilization, these primary aneuploid cells become cytological unstable, generating diverse karyotypic mosaic embryos. The mosaic aneuploid embryos can develop and implant into the female uterine tissue and initiate the gastrulation process (E6.5) but quickly degrade and succumb by E8.0. We find that loss of embryo viability due to chromosomal mosaicism is caused by the activation of a spatially and temporally controlled p53-independent apoptotic mechanism and does not result from a failure to progress through mitosis. We conclude that an initial state of primary aneuploidy within an embryo results in a rapid evolution of mosaicism and early embryonic death. This gestational loss due to aneuploid mosaicism could account for the large proportion of human pregnancy loss prior to clinical recognition.

No abstract

Karyotypic analyses of Down syndrome patients have identified a low level of chromosome mosaicism, suggesting that the primary aneuploid status of the cells promotes further chromosomal segregation errors. Sycp3-null female mice produce aneuploid oocytes, which after fusion with normal haploid sperm, result in offspring with systemic whole chromosome, aneuploid embryo cells. Using the Sycp3-null female as a model, we observe an increase in the number of embryonic cells at E7.0 that exhibit abnormal chromosomal bridges at the anaphas estage of mitosis. This result suggests that global changes in gene expression patterns resulting from primary aneuploidy can affect mitotic chromosome segregation, resulting in a low level of chromosomal instability. The increased level of chromosomal instability could in the absence of mitotic checkpoints, lead to chromosomal mosaicism within the adult organism, as seen in Down syndrome patients.