Mechanisms of nondisjunction: facts and perspectives

An ordered segregation requires distinct processes of differentiation within the germ cell for recognition and segregation of homologous chromosomes/chromatids. These include synchronous maturation of the nucleus and cytoplasm, chromosome pairing and assembly at the metaphase plate, and movement within the spindle; all of them may be under direct/indirect regulatory control by the surrounding somatic compartments. Interference, e.g., by hormonal alterations at any of these steps, may alter the normal program of differentiation, thus increasing the risk of chromosomal malsegregation. Hence, many different causative mechanisms may exist which basically, nevertheless, act via (a) nonsegregation, (b) chance segregation, both during meiosis 1 and 2, or (c) presegregation during meiosis 1. In our animal models of the Djungarian hamster and the NMRI/Han mouse strain, we are analyzing the mechanisms of nondisjunction and presegregation during meiosis 1 in oocytes, as well as during aging of the females, by the application of hormones (gonadotrophins and steroids) and specific microtubular inhibitors (colchicine and methylbenzimidazolcarbamate). We suggest that chromosomes play a relatively passive role, although chromosomal properties, e.g., length, chiasma number, NORs, and position within the spindle, may provide an individual risk for each bivalent to be affected by nondisjunction. Failures in the endocrine control of follicular and germ cell maturation are considered to be primary causes for nondisjunction in young and aging oocytes. The understanding of the differentiation processes resulting in the maturation of follicles "at risk" may provide us with the tool to prevent the generation of aneuploidy in man.