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Meiotic arrest and aneuploidy in MLH3-deficient mice

Nature Genetics volume 31, pages 385–390 (2002)Cite this article

Abstract

MutL homolog 3 (Mlh3) is a member of a family of proteins conserved during evolution and having dual roles in DNA mismatch repair and meiosis1,2. The pathway in eukaryotes consists of the DNA-binding components, which are the homologs of the bacterial MutS protein (MSH 2–6), and the MutL homologs, which bind to the MutS homologs and are essential for the repair process. Three of the six homologs of MutS that function in these processes, Msh2, Msh3 and Msh6, are involved in the mismatch repair of mutations, frameshifts and replication errors2,3, and two others, Msh4 and Msh5, have specific roles in meiosis4,5,6,7,8,9,10. Of the four MutL homologs, Mlh1, Mlh3, Pms1 and Pms2, three are involved in mismatch repair and at least two, Pms2 and Mlh1, are essential for meiotic progression in both yeast and mice2,3,11,12,13,14. To assess the role of Mlh3 in mammalian meiosis, we have generated and characterized Mlh3−/− mice15. Here we show that Mlh3−/− mice are viable but sterile. Mlh3 is required for Mlh1 binding to meiotic chromosomes and localizes to meiotic chromosomes from the mid pachynema stage of prophase I. Mlh3−/− spermatocytes reach metaphase before succumbing to apoptosis, but oocytes fail to complete meiosis I after fertilization. Our results show that Mlh3 has an essential and distinct role in mammalian meiosis.

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Figure 1: Localization of Mlh3 to male mouse chromosomes at pachynema and diplonema stages of meiosis I.
Figure 2: Generation of Mlh3-null mice.
Figure 3: Testicular histology of wildtype (left panels) and Mlh3−/− male mice (middle and right panels).
Figure 4: Normal chromosomal synapsis in spermatocytes from adult Mlh3−/− male mice is followed by failure to maintain homologous pairing at metaphase.
Figure 5: Electron micrographs of surface-spread chromosomes.
Figure 6: Normal ovarian morphology in Mlh3−/− female mice and localization of Mlh3 on chromosomes from ovaries of embryonic day 19 females.

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Acknowledgements

We thank G. Elliott and A. Becker for help with mouse studies; M. Liskay and W. Edelmann for critically reading this manuscript; G. Enders for antibodies; and N. Kolas for discussions and advice. This work was supported by the Albert Einstein College of Medicine (P.E.C.), National Human Genome Research Institute intramural funds and New Faculty start-up funds through the University of California, Irvine (S.M.L.).

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, University of California, Irvine, 92697, California, USA

    Steven M. Lipkin

  2. Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA

    Steven M. Lipkin, Victoria Wang, Dakshine Shanmugarajah & Francis S. Collins

  3. Department of Biology, University of York, Toronto, M3J 1P3, Ontario, Canada

    Peter B. Moens

  4. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, USA

    Michelle Lenzi, Abigail Gilgeous & Paula E. Cohen

  5. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA

    Dakshine Shanmugarajah, James Thomas, Jeffrey W. Touchman, Eric D. Green & Francis S. Collins

  6. Transgenic and Knock-out Core Facility, National Human Genome Research Institute, Bethesda, Maryland, USA

    Jun Cheng & Pam Schwartzberg

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Correspondence to Steven M. Lipkin or Paula E. Cohen.

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Lipkin, S., Moens, P., Wang, V. et al. Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31, 385–390 (2002). https://doi.org/10.1038/ng931

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