Chromosomal influence on meiotic spindle assembly: Abnormal meiosis I in female Mlh1 mutant mice

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 th e meiotic spindle, it remains unclear how a stable bipolar spindle is estab lished. We have studied the formation of the first meiotic spindle in murin e oocytes from mice homozygous for a targeted disruption of the DNA mismatc h repair gene, Mlh1. In the absence of the MLH1 protein meiotic recombinati on is dramatically reduced and, as a result, the vast majority of chromosom es are present as unpaired univalents at the first meiotic division. The or ientation 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 indivi dual sister chromatids. In the presence of this aberrant chromosome behavio r 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 chro mosomes not only promote microtubule polymerization and organization but th eir attachment to opposite spindle poles acts to stabilize the forming spin dle poles.