Gamete Biology

Comparative Analysis of Meiotic Progression in Female Mice Bearing Mutations in Genes of the DNA Mismatch Repair Pathway

Abstract
The DNA mismatch repair (MMR) family functions in a variety of contexts to preserve genome integrity in most eukaryotes. In particular, members of the MMR family are involved in the process of meiotic recombination in germ cells. MMR gene mutations in mice result in meiotic disruption during prophase I, but the extent of this disruption often differs between male and female meiocytes. To address the role of MMR proteins specifically in female meiosis, we explored the progression of oocytes through prophase I and the meiotic divisions in mice harboring deletions in members of the MMR pathway (Mlh1, Mlh3, Exo1 and an ATPase-deficient variant of Mlh1, Mlh1^G67R). The co-localization of MLH1 and MLH3, key proteins involved in stabilization of nascent crossovers, was dependent on intact heterodimer formation, and was highly correlated with the ability of oocytes to progress through to metaphase II. The exception was Exo1^-/- oocytes, in which normal MLH1/MLH3 localization was observed followed by failure to proceed to metaphase II. All mutant oocytes were able to resume meiosis after dictyate arrest, but showed a dramatic decline in chiasmata (to less than 25% of normal), accompanied by varied progression through metaphase I. Taken together, these results demonstrate that MMR function is required for the formation and stabilization of crossovers and that, in the absence of a functional MMR system, the failure to maintain chiasmata results in reduced ability to proceed normally through the first and second meiotic divisions, despite near normal levels of meiotic resumption after dictyate arrest.

Key words: Gamete Biology • Ovary • Gametogenesis • Meiosis • Oocyte development

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				A. Svetlanov, F. Baudat, P. E. Cohen, and B. de Massy Distinct Functions of MLH3 at Recombination Hot Spots in the Mouse Genetics, April 1, 2008; 178(4): 1937 - 1945. [Abstract] [Full Text] [PDF]