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Mammalian MutS homologue 5 is required for chromosome pairing in meiosis

Nature Genetics volume 21, pages 123–127 (1999)Cite this article

Abstract

MSH5 (MutS homologue 5) is a member of a family of proteins known to be involved in DNA mismatch repair1,2. Germline mutations in MSH2, MLH1 and GTBP (also known as MSH6) cause hereditary non–polyposis colon cancer (HNPCC) or Lynch syndrome3,4,5,6,7,8. Inactivation of Msh2, Mlh1, Gtmbp (also known as Msh6) or Pms2 in mice leads to hereditary predisposition to intestinal and other cancers9,10,11,12,13,14. Early studies in yeast revealed a role for some of these proteins, including Msh5, in meiosis15,16,17. Gene targeting studies in mice confirmed roles for Mlh1 and Pms2 in mammalian meiosis12,13,14,18. To assess the role of Msh5 in mammals, we generated and characterized mice with a null mutation in Msh5. Msh5–/– mice are viable but sterile. Meiosis in these mice is affected due to the disruption of chromosome pairing in prophase I. We found that this meiotic failure leads to a diminution in testicular size and a complete loss of ovarian structures. Our results show that normal Msh5 function is essential for meiotic progression and, in females, gonadal maintenance.

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Figure 1: Generation of Msh5 –null mice.
Figure 2: Disruption of spermatogenesis in Msh5–/– males.
Figure 3: Progressive depletion of germ cells in Msh5–/– males during development.
Figure 4: Disruption of meiosis before synapsis in Msh5–/– spermatocytes.
Figure 5: Loss of oocytes and subsequent ovarian degeneration in Msh5–/– females.
Figure 6: Disruption of oogenesis in Msh5–/– females leads to a failure of folliculogenesis.

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Acknowledgements

We thank the following colleagues for generously providing antibodies and advice: P. Moens, B. Spyropoulos and G. Enders. The expert technical assistance of H. Hou Jr, L. Zhu and members of the AECOM Analytical Imaging Facility (F. Maculuso, L. Gunther and C. Marks) is appreciated. We also thank S. Shenoy for training and help with the CCD imaging system. This work was supported by NIH grants (CA 76329 to W.E.; CA 67944 and NO1–CN–65031 to R.K.; CA 44704 to R.D.K.), the American Cancer Society (R.K.) and a Cancer Center grant to AECOM (CA13330).

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  1. Winfried Edelmann and Paula E. Cohen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Winfried Edelmann & Burkhard Kneitz

  2. Department of Developmental and Molecular Biology Albert Einstein College of Medicine, 1300 Morris Park Avenue , Bronx, 10461, New York, USA

    Paula E. Cohen & Jeffrey W. Pollard

  3. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Marie Lia, Joerg Heyer & Raju Kucherlapati

  4. Dana Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Nena Winand & Richard Kolodner

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Correspondence to Winfried Edelmann.

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Edelmann, W., Cohen, P., Kneitz, B. et al. Mammalian MutS homologue 5 is required for chromosome pairing in meiosis . Nat Genet 21, 123–127 (1999). https://doi.org/10.1038/5075

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