Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Silencing of unsynapsed meiotic chromosomes in the mouse

Nature Genetics volume 37, pages 41–47 (2005)Cite this article

Abstract

In Neurospora, DNA unpaired in meiosis both is silenced and induces silencing of all DNA homologous to it. This process, called meiotic silencing by unpaired DNA, is thought to protect the host genome from invasion by transposable elements. We now show that silencing of unpaired (unsynapsed) chromosome regions also takes place in the mouse during both male and female meiosis. The tumor suppressor protein BRCA1 is implicated in this silencing, mirroring its role in the meiotic silencing of the X and Y chromosomes in normal male meiosis. These findings impact on the interpretation of the relationship between synaptic errors and sterility in mammals and extend our understanding of the biology of Brca1.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Localization of BRCA1, ATR and γH2AX in XO oocytes.
Figure 2: Localization of BRCA1, ATR and γH2AX in XX oocytes.
Figure 3: Localization of BRCA1, ATR and γH2AX in chain quadrivalent and bivalent-bivalent configurations in T(X;16)16H spermatocytes.
Figure 4: Localization of ATR and γH2AX in asynaptic Brca1Δ11/Δ11 Trp53+/− and Trp53+/− (control) spermatocytes.
Figure 5: Localization of ATR and γH2AX and MSCI in Atm-null spermatocytes.
Figure 6: Transcriptional repression of unsynapsed chromosomes in XO oocytes (γH2AX, green; Cot-1 probe, red; colocalization, yellow).
Figure 7: Transcriptional repression of unsynapsed chromosome segments in T(X;16)16H spermatocytes.

Similar content being viewed by others

References

  1. Zickler, D. & Kleckner, N. Meiotic chromosomes: integrating structure and function. Annu. Rev. Genet. 33, 603–754 (1999).

    Article  CAS  Google Scholar 

  2. de Boer, P. & de Jong, J.H. Chromosome pairing and fertility in mice. in Fertility and Chromosome Pairing: Recent Studies in Plants and Animals (ed. Gillies, C.B.) 37–76 (CRC Press, Boca Raton, Florida, 1989).

    Google Scholar 

  3. Burgoyne, P.S. & Mahadevaiah, S.K. Unpaired sex chromosomes and gametogenic failure. Chromosomes Today 11, 243–263 (1993).

    Article  CAS  Google Scholar 

  4. Miklos, G.L.G. Sex chromosome pairing and male fertility. Cytogenet. Cell Genet. 13, 558–577 (1974).

    Article  CAS  Google Scholar 

  5. Burgoyne, P.S. & Baker, T.G. Meiotic pairing and gametogenic failure. in Controlling Events in Meiosis, 38th Symposium of the Society for Experimental Biology (ed. Dickinson, H.G.) 349–362 (The Company of Biologists Ltd, Cambridge, 1984).

    Google Scholar 

  6. Roeder, S. & Bailis, J.M. The pachytene checkpoint. Trends Genet. 16, 395–403 (2000).

    Article  CAS  Google Scholar 

  7. Xu, L., Weiner, B.M. & Kleckner, N. Meiotic cells monitor the status of the interhomolog recombination complex. Genes Dev. 11, 106–118 (1997).

    Article  CAS  Google Scholar 

  8. Anderson, L.K., Stack, S.M. & Sherman, J.D. Spreading synaptonemal complexes from Zea mays. I. No synaptic adjustment of inversion loops during pachytene. Chromosoma 96, 295–305 (1988).

    Article  CAS  Google Scholar 

  9. Moens, P.B. et al. The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination. J. Cell Sci. 115, 1611–1622 (2002).

    CAS  PubMed  Google Scholar 

  10. Plug, A.W. et al. Changes in protein composition of meiotic nodules during mammalian meiosis. J. Cell Sci. 111, 413–423 (1998).

    CAS  PubMed  Google Scholar 

  11. Ashley, T. An integration of old and new perspectives of mammalian meiotic sterility. in Results and Problems in Cell Differentiation vol. 28 (ed. McElreavey, K.) 131–173 (Springer, Berlin, Heidelberg, 2000).

    Google Scholar 

  12. Keegan, K.S. et al. The Atr and Atm protein kinases associate with different sites along meiotically pairing chromosomes. Genes Dev. 10, 2423–2437 (1996).

    Article  CAS  Google Scholar 

  13. Moens, P.B. et al. The association of ATR protein with mouse meiotic chromosome cores. Chromosoma 108, 95–102 (1999).

    Article  CAS  Google Scholar 

  14. Scully, R. et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88, 265–275 (1997).

    Article  CAS  Google Scholar 

  15. Turner, J.M.A. et al. BRCA1, histone H2AX phosphorylation and male meiotic sex chromosome inactivation. Curr. Biol. (in the press).

  16. Shiu, P.K., Raju, N.B., Zickler, D. & Metzenberg, R.L. Meiotic silencing by unpaired DNA. Cell 107, 905–916 (2001).

    Article  CAS  Google Scholar 

  17. Lammers, J.H.M. et al. The gene encoding a major component of synaptonemal complexes of rat is related to X-linked lymphocyte-regulated genes. Mol. Cell. Biol. 14, 1137–1146 (1994).

    Article  CAS  Google Scholar 

  18. Lyon, M.F. & Hawker, S.G. Reproductive lifespan in irradiated and unirradiated chromosomally XO mice. Genet. Res. 21, 185–194 (1973).

    Article  CAS  Google Scholar 

  19. Burgoyne, P.S. & Baker, T.G. Oocyte depletion in XO mice and their XX sibs from 12 to 200 days post partum. J. Reprod. Fertil. 61, 207–212 (1981).

    Article  CAS  Google Scholar 

  20. Burgoyne, P.S. & Baker, T.G. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J. Reprod. Fertil. 75, 633–645 (1985).

    Article  CAS  Google Scholar 

  21. Speed, R.M. Oocyte development in XO foetuses of man and mouse: the possible role of heterologous X-chromosome pairing in germ cell survival. Chromosoma 94, 115–124 (1986).

    Article  CAS  Google Scholar 

  22. Ford, C.E. & Evans, E.P. A reciprocal translocation in the mouse between the X chromosome and a short autosome. Cytogenetics 3, 295–305 (1964).

    Article  CAS  Google Scholar 

  23. Odorisio, T., Rodriguez, T.A., Evans, E.P., Clarke, A.R. & Burgoyne, P.S. The meiotic checkpoint monitoring synapsis eliminates spermatocytes via p53-independent apoptosis. Nat. Genet. 18, 257–261 (1998).

    Article  CAS  Google Scholar 

  24. Xu, X., Aprelikova, O., Moens, P., Deng, C.X. & Furth, P.A. Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Development 130, 2001–2012 (2003).

    Article  CAS  Google Scholar 

  25. Xu, X. et al. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat. Genet. 28, 266–271 (2001).

    Article  CAS  Google Scholar 

  26. Mahadevaiah, S.K. et al. Recombinational DNA double-strand breaks in mice precede synapsis. Nat. Genet. 27, 271–276 (2001).

    Article  CAS  Google Scholar 

  27. Fernandez-Capetillo, O., Liebe, B., Scherthan, H. & Nussenzweig, A. H2AX regulates meiotic telomere clustering. J. Cell Biol. 163, 15–20 (2003).

    Article  CAS  Google Scholar 

  28. Hall, L.L. et al. An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells. Proc. Natl Acad. Sci. USA 99, 8677–8682 (2002).

    Article  CAS  Google Scholar 

  29. Huynh, K.D. & Lee, J.T. Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature 426, 857–862 (2003).

    Article  CAS  Google Scholar 

  30. Moore, G.P. DNA-dependent RNA synthesis in fixed cells during spermatogenesis in mouse. Exp. Cell Res. 68, 462–465 (1971).

    Article  CAS  Google Scholar 

  31. Handel, M.A. The XY body: a specialized meiotic chromatin domain. Exp. Cell Res. 296, 57–63 (2004).

    Article  CAS  Google Scholar 

  32. Turner, J.M.A. et al. Analysis of male meiotic “sex-body” proteins during XY female meiosis provides new insights into their functions. Chromosoma 109, 426–432 (2000).

    Article  CAS  Google Scholar 

  33. Wang, P.J. X chromosomes, retrogenes and their role in male reproduction. Trends Endocrinol. Metab. 15, 79–83 (2004).

    Article  Google Scholar 

  34. Bean, C.J., Schaner, C.E. & Kelly, W.G. Meiotic pairing and imprinted X chromatin assembly in Caenorhabditis elegans. Nat. Genet. 36, 100–105 (2004).

    Article  CAS  Google Scholar 

  35. Baarends, W.M. et al. Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis. Mol. Cell Biol. (in the press).

  36. Mahadevaiah, S.K., Lovell-Badge, R. & Burgoyne, P.S. Tdy-negative XY, XXY and XYY female mice: breeding data and synaptonemal complex analysis. J. Reprod. Fertil. 97, 151–160 (1993).

    Article  CAS  Google Scholar 

  37. Peters, A.H., Plug, A.W. & de Boer, P. Meiosis in carriers of heteromorphic bivalents: sex differences and implications for male fertility. Chromosome Res. 5, 313–324 (1997).

    Article  CAS  Google Scholar 

  38. Burgoyne, P.S. & Evans, E.P. A high frequency of XO offspring from XPafY* male mice: evidence that the Paf mutation involves an inversion spanning the X PAR boundary. Cytogenet. Cell Genet. 91, 57–61 (2000).

    Article  CAS  Google Scholar 

  39. Xu, X. et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat. Genet. 22, 37–43 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Heyting and W. Earnshaw for providing antibody reagents; T. Nesterova, L. Hall and J Lawrence for advice on RNA FISH; O. Ojarikre for mouse breeding; and H. Byers for critical reading of the manuscript. J.M.A.T. is an MRC Career Development Fellow.

Author information

Authors and Affiliations

  1. Division of Stem Cell Research and Developmental Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    James M A Turner, Shantha K Mahadevaiah & Paul S Burgoyne

  2. Experimental Immunology Branch, National Cancer Institute, National Institute of Diabetes, Digestive and Kidney Diseases, Building 10, 9N105, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Oscar Fernandez-Capetillo & André Nussenzweig

  3. Genetics of Development and Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Building 10, 9N105, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Xiaoling Xu & Chu-Xia Deng

Authors
  1. James M A Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shantha K Mahadevaiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oscar Fernandez-Capetillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. André Nussenzweig
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoling Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chu-Xia Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul S Burgoyne
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James M A Turner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Transcription patterns during male meiosis as revealed by Cot-1 RNA FISH and γH2AX and CREST immunostaining. (PDF 10 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Turner, J., Mahadevaiah, S., Fernandez-Capetillo, O. et al. Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet 37, 41–47 (2005). https://doi.org/10.1038/ng1484

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1484

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing