The investigation of factors affecting chromosome segregation during female meiosis.

摘要

An estimated 10--25% of all human conceptuses are aneuploid, resulting in devastating clinical consequences. Although little is known about the origin of aneuploidy, most errors have been attributed to the maternal first meiotic division (MI). The first meiotic division is a specialized cell division that requires the modified action of two chromosome-associated protein complexes, the kinetochore and sister chromatid cohesion. The objective of this thesis was to investigate factors that affect sister kinetochore function and sister chromatid cohesion during MI to gain a better understanding of female meiosis and nondisjunction.;Precocious sister chromatid segregation (PSCS) at MI has been postulated to be a major contributor to human nondisjunction. To investigate factors affecting PSCS, we used the XO mouse as a model since the sister chromatids of the single X chromosome frequently segregate at MI and the propensity for PSCS is influenced by genetic background. Our analysis demonstrated that differences in PSCS between strains was due to the action of an autosomal trans-acting factor or factors. Our studies also showed that this factor does not involve synapsis since we were unable to correlate synapsis with PSCS. Finally, we demonstrated that, contrary to expectation, sister kinetochore morphology does not predict sister kinetochore function.;During our investigation of factors affecting chromosome segregation in the female, we observed a sexual dimorphism in centromere-associated proteins. Two protein components of the synaptonemal complex, SCP2 and SCP3, and the meiosis-specific cohesin, SMC1beta, had all previously been reported to persist at the centromere until anaphase II during meiosis in the male. However, in the female we found that these proteins gradually disappear during dictyate arrest and are undetectable at subsequent meiotic divisions. Given the postulated role of these centromere-associated proteins in chromosome segregation, we hypothesize that this sexual dimorphism could provide an explanation for the difference in error frequency between male and female meiosis.;Lastly, in the course of these studies, a new technique that provides simultaneous cytological analysis of chromosome-associated proteins and chromosome number in oocytes and early embryos was developed. This technique provides a new means of understanding the relationship between chromosome-associated proteins and nondisjunction.