Chromosomal Influence on Meiotic Spindle Assembly: Abnormal Meiosis I in Female Mlh1 Mutant Mice

Abstract

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.

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…MLH1 −/− fibroblaste also are MSI-high and deficient in MMR. In contrast to the MSH2 −/− mice, MLH1 −/− males and females are sterile (Edelmann et al, 1996;Woods et al, 1999). Germ line cells in MLH1 −/− male mice enter meiotic prophase, arrest at pachytene phase, and undergo apoptosis.…”

Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis

“…In principle, a perfect correlation between the numbers of Mlh1 foci and CO is not necessarily expected given the potential existence of a Mlh1-independent CO pathway, as shown in S. cerevisiae for instance. In fact, in mice, Mlh1 is required for the formation of most, but not all, CO given the 10Y20-fold reduction of CO frequencies in Mlh1j/j mice, which have therefore a residual level of CO activity corresponding to 5Y10% of wild-type (Woods et al 1999, Guillon et al 2005. We note a slight excess of CO as measured genetically as compared to Mlh1 foci in wild-type mice, which could be due to technical bias or to the presence of a small proportion of Mlh1-independent CO in wild-type mice (Table 1).…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…68 As defects of other meiotic genes are reported to induce aneuploidy in oocytes in female mice, it is possible that these genes also contribute to the susceptibility to aneuploidy in humans. 69,70 In relation to SYCP3, it is of interest that a mutation in this gene was also identified in two human patients with azoospermia. 71 Indeed, male mice that are deficient in SYCP3 are sterile due to the onset of meiotic arrest.…”