| Although human aneuploidy has an important clinical role in pregnancy loss and birth defects, little is understood about its underlying mechanisms. Mouse models aid studies of human aneuploidy by making possible experiments and observations which are impossible in humans. In general, descriptions of mice with a “high-nondisjunction” phenotype are limited, and reports of strain specific influences on mammalian chromosome segregation are exceedingly rare.; The Wt Y chromosome represents a rare example of an apparently structurally normal mammalian chromosome that is nevertheless prone to a high incidence of a spontaneous, recurring, mitotic nondisjunction. The experiments described in this thesis are designed to achieve two closely related objectives. Initial studies focus on carefully characterizing the timing and incidence of Wt Y missegregation during early development, while subsequent studies focus on using this segregation-impaired chromosome to uncover evidence for genetic and environmental factors that alter mammalian chromosome segregation.; Our results indicate that the Wt Y chromosome is stably transmitted during meiotic cell divisions, but nondisjoins at an extremely high frequency in mitosis. Surprisingly, the post-zygotic nondisjunction events are largely restricted to the first two cleavage divisions, indicating that there is a temporal window during which the Wt Y chromosome is susceptible to nondisjunction. Further, our observations of an excess of hypodiploid cells in mid-gestation fetuses and Y-bearing micronuclei associated with mosaic preimplantation embryos indicate that the process frequently results in chromosome loss rather than true nondisjunction.; While it is clear that the Wt Y is a vulnerable chromosome, it is also clear that this vulnerability depends in vivo and in vitro on trans-acting factors. The incidence of nondisjunction in vivo was significantly influenced by maternal strain background, demonstrating evidence for a genetic effect on mammalian nondisjunction. Additionally, we observed a highly significant variation in the incidence of Wt Y chromosome missegregation in embryos derived in vitro under altered culture conditions. Our results suggest that the earliest cleavage divisions in mammals are nondisjunction-prone and that slight alterations in maternally supplied factors in vivo or embryo culture conditions in vitro may have a dramatic impact on chromosome segregation. |
