Mosaic variegated aneuploidy in mouse BubR1 deficient embryos and pregnancy loss in human
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Chromosome aberrations (aneuploidies mostly) are the cause of the majority of spontaneous abortions in humans. However, little is known about defects in the underlying molecular mechanisms resulting in chromosome aberrations and following failure of preimplantation embryo development, initiation of implantation and postimplantation pregnancy loss. We suggest that defects of the spindle assembly checkpoint (SAC) are responsible for aneuploidy and the following abortions. To develop our hypothesis, we modeled this process in the mouse after inactivation of protein BubR1, one of the key players of SAC. We found that soon after implantation, more than 50 % of cells of BubR1 −/− embryos were aneuploid and had an increased level of premature sister chromatid separation (PSCS). Aneuploid cells do not have a predominant gain or loss of some specific chromosomes, but they have mosaic variegated aneuploidy (MVA), which is characterised by random mixture of different chromosomes. MVA leads to growth retardation, stochastic massive apoptosis, disruption of bilateral symmetry, and embryo death between embryonic days 7.5 to 13.5. Analysis published human data revealed that human recurrent pregnancy loss (RPL) embryos and rare infant patients carrying BubR1 mutations that have been described so far have the PSCS and MVA as in BubR1 deficient/insufficient mice. Based on this data, we predict that deficiency/insufficiency of BubR1 and other components of the SAC in human are responsible for a significant fraction of both early and late RPLs.
KeywordsSpindle assembly checkpoint BubR1 deficiency Mosaic variegated aneuploidy Pregnancy loss
Fluorescence in situ hybridization
In vitro fertilization
Mouse embryonic fibroblasts
Mosaic variegated aneuploidy
Premature sister chromatid separation
Recurrent pregnancy loss
Spindle assembly checkpoint
We gratefully acknowledge Winfried Edelmann, for providing advices. We thank Cornelia Leimeister, Barbara Zoeller and Galina Fedorova for expert technical assistance. We acknowledge Pamela Stanley for WW-6 ES cells. We are grateful to David Battaglia, Alexander Derkatch, Daniel Marks and Matt Thayer for critical reading of the manuscript and the helpful discussions. This work was partly supported, by the IZKF of the University of Wuerzburg, Germany and by the Office of the Vice President for Research, Oregon Health & Science University, Portland, OR, USA.