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Comparative Analysis of Meiotic Progression in Female Mice Bearing Mutations in Genes of the DNA Mismatch Repair Pathway¹

Department of Biomedical Sciences,⁴ Cornell University College of Veterinary Medicine, Ithaca, New York 14850 Department of Cell Biology,⁵ Albert Einstein College of Medicine, Bronx, New York 10461 Theodor-Boveri-Institut für Biowissenschaften,⁶ Bayerische Julius-Maximilians-Universität, 97074 Würzburg, Germany

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 colocalization 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 they 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 in mammalian oocytes and that, in the absence of a functional MMR system, the failure to maintain chiasmata results in a reduced ability to proceed normally through the first and second meiotic divisions, despite near-normal levels of meiotic resumption after dictyate arrest.

gamete biology, gametogenesis, meiosis, mismatch repair, oocyte development, ovary, recombination, synaptonemal complex

³Current address: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.

¹Supported by funding from NIH to P.E.C. (HD041012).

Correspondence: ²FAX: 607 253 4495; e-mail: pc242{at}cornell.edu

This article has been cited by other articles:

				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]