The fate of primary aneuploid cells in early embryonic development and stem cells

Abstract: Chromosomal aberrations occurring during gametogenesis and early embryonic development play a significant role in infertility and fetal loss in humans. Germ cells that have an abnormal number of chromosomes (aneuploidy) are generated mainly due to errors during female gamete formation, a phenomenon increasing in occurrence with age. As methods such as in-vitro fertilization, pre-implantation genetic diagnosis, and embryonic stem cell transplantations are increasingly utilized to address a modern dilemma of infertility in humans, it underscores an urgent need to further understand the origins and consequences of chromosomal abnormalities in germ cells. Removal of the meiosis specific gene encoding SYCP3, a conserved major structural component of the synaptonemal complex in mice, incites chromosomal errors in both male and female gamete production. We have here studied the consequences of such errors and their effects on fertility within an established mouse model system. Male mice lacking Sycp3 have been previously shown to be sterile. By crossing Sycp3-/- with a Trp53-/- strain, we show that p53, a known regulator of programmed cell death in many cell lineages, fails to inhibit this apoptotic process in spermatocytes. We conclude that the apoptotic mechanism that responds to meiotic disruption and partial asynapsis, resulting in Sycp3-/- male infertility is p53 independent. As asynapsed chromosome pairing during meioisis is attributed as the foremost cause of germ cell death in infertile men, our mouse model provides a key insight into the regulation of compromised male meiotic cells. Unlike male germ cells, the oocyte is more disposed to errors in the production of viable gametes. The Sycp3-/- female mouse is semi-fertile and produces mature haploid aneuploid oocytes, which after fusion with healthy sperm, results in the production of offspring with systemic aneuploid embryo cells. We have studied the fate of the mouse embryos that results from the fertilization process of these karyotypically abnormal oocytes. We find that primary aneuploid embryos are capable of early embryonic development despite an evolving state of mosaicism. These embryos however succumb during gastrulation, due to a spatially and temporally controlled apoptotic mechanism that is p53-independent. We conclude that primary aneuploid embryos are cytological unstable, forming cytological chaotic mosaic states within the embryo leading to its developmental loss. As almost two thirds of all in-vitro fertilization treatments result in early spontaneous abortions, with a large proportion of these being a result from abnormal embryo karyotypes, our mouse model could further help elucidate the mechanisms resulting in infertility as a result from early embryonic loss. In-vitro models that recapitulate the germ cell differentiation process would greatly facilitate academic research and would be beneficial for therapeutic uses such as infertility. We pursued the possibility of generating mouse oocytes in culture by selective differentiation of pluripotent embryonic stem cells (ESCs). Though in-vitro differentiation of ESC’s generated estradiol producing ovarian follicle-like structures, their meiotic process was shown to be highly aberrant. Our results suggest that while several aspects of the germ cell differentiating process can be recapitulated in culture, more work is required before we have the capacity to generate germ cells in-vitro. Understanding aneuploidy within a mammalian model offers great insight into human conditions and current medical dilemmas. By using the Sycp3-null mouse model system, we can now provide a better understanding of the effects of primary aneuploidy on fertility, its effect on developing early embryos and more precisely define the fate of mosaic aneuploid chromosome cells in a mammalian system.