Craig A. Hodges

In mouse oocytes, the first meiotic spindle is formed through the action of multiple microtubule organizing centers rather than a pair of centrosomes. Although the chromosomes are thought to play a major role in organizing the meiotic spindle, it remains unclear how a stable bipolar spindle is established. We have studied the formation of the first meiotic spindle in murine oocytes from mice homozygous for a targeted disruption of the DNA mismatch repair gene, Mlh1. In the absence of the MLH1 protein meiotic recombination is dramatically reduced and, as a result, the vast majority of chromosomes are present as unpaired univalents at the first meiotic division. The orientation of these univalent chromosomes at prometaphase suggests that they are unable to establish stable bipolar spindle attachments, presumably due to the inability to differentiate functional kinetochore domains on individual sister chromatids. In the presence of this aberrant chromosome behavior a stable first meiotic spindle is not formed, the spindle poles continue to elongate, and the vast majority of cells never initiate anaphase. These results suggest that, in female meiotic systems in which spindle formation is based on the action of multiple microtubule organizing centers, the chromosomes not only promote microtubule polymerization and organization but their attachment to opposite spindle poles acts to stabilize the forming spindle poles.

BACKGROUND: It is well known that the fidelity of meiotic chromosome segregation is greatly reduced with increasing maternal age in humans. More recently, direct studies of human oocytes have demonstrated a striking age-related increase in oocytes exhibiting gross disturbances in chromosome alignment on the meiotic spindle. This abnormality, termed congression failure, has been postulated to be causally related to human non-disjunction and to result from subtle alterations in folliculogenesis that develop with advancing reproductive age. METHODS: Immunofluorescence staining, conventional cytogenetic analysis and spectral karyotyping of oocytes from mouse models were used to investigate the hypothesis that changes in the regulation of folliculogenesis induce meiotic defects. RESULTS: Mutations that affect oocyte growth were found to increase the frequency of congression failure at first meiotic metaphase. Importantly, increased congression failure was correlated with meiotic non-disjunction, suggesting a cause-and-effect relationship. CONCLUSIONS: Our findings support the hypothesis that congression failure results from disturbances in the complex interplay of signals regulating folliculogenesis and that these changes subtly alter the late stages of oocyte growth, increasing the risk of a non-disjunction error. These findings have important implications for human aneuploidy, since they suggest that it may be possible to develop prophylactic treatments for reducing the risk of age-related aneuploidy.