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.

  • Letter
  • Published:

BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice

Nature Genetics volume 36, pages 744–749 (2004)Cite this article

Abstract

Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Cachectic dwarfism and short lifespan in BubR1-insufficient mice.
Figure 2: Aging phenotypes in Bub1bH/H mice.
Figure 3: Bub1bH/H cells have mitotic checkpoint defects.
Figure 4: BubR1 insufficiency causes early onset of senescence.
Figure 5: Analysis of BubR1 in testis and ovary of mutant and normal mice.

Similar content being viewed by others

References

  1. Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280–291 (2001).

    Article  CAS  Google Scholar 

  2. Thomas, N.S. et al. Maternal sex chromosome non-disjunction: evidence for X chromosome-specific risk factors. Hum. Mol. Genet. 10, 243–250 (2001).

    Article  CAS  Google Scholar 

  3. Jallepalli, P.V. & Lengauer, C. Chromosome segregation and cancer: cutting through the mystery. Nat. Rev. Cancer 1, 109–117 (2001).

    Article  CAS  Google Scholar 

  4. Wassmann, K. & Benezra, R. Mitotic checkpoints: from yeast to cancer. Curr. Opin. Genet. Dev. 11, 83–90 (2001).

    Article  CAS  Google Scholar 

  5. Yu, H. Regulation of APC-Cdc20 by the spindle checkpoint. Curr. Opin. Cell Biol. 14, 706–714 (2002).

    Article  CAS  Google Scholar 

  6. Cleveland, D.W., Mao, Y. & Sullivan, K.F. Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112, 407–421 (2003).

    Article  CAS  Google Scholar 

  7. Wang, Q. et al. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood 103, 1278–1285 (2004).

    Article  CAS  Google Scholar 

  8. Babu, J.R. et al. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J. Cell Biol. 160, 341–353 (2003).

    Article  CAS  Google Scholar 

  9. Michel, L.S. et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409, 355–359 (2001).

    Article  CAS  Google Scholar 

  10. Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).

    Article  CAS  Google Scholar 

  11. Campisi, J. Cancer and ageing: rival demons? Nat. Rev. Cancer 3, 339–349 (2003).

    Article  CAS  Google Scholar 

  12. Parrinello, S. et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell Biol. 5, 741–747 (2003).

    Article  CAS  Google Scholar 

  13. Lengauer, C., Kinzler, K.W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  Google Scholar 

  14. Li, R., Sonik, A., Stindl, R., Rasnick, D. & Duesberg, P. Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proc. Natl. Acad. Sci. USA 97, 3236–3241 (2000).

    Article  CAS  Google Scholar 

  15. Cahill, D.P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998).

    Article  CAS  Google Scholar 

  16. Shichiri, M., Yoshinaga, K., Hisatomi, H., Sugihara, K. & Hirata, Y. Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival. Cancer Res. 62, 13–17 (2002).

    CAS  PubMed  Google Scholar 

  17. Ford, W.C. et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood). Hum. Reprod. 15, 1703–1708 (2000).

    Article  CAS  Google Scholar 

  18. Eskenazi, B. et al. The association of age and semen quality in healthy men. Hum. Reprod. 18, 447–454 (2003).

    Article  CAS  Google Scholar 

  19. Meyers, E.N., Lewandoski, M. & Martin, G.R. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nat. Genet. 18, 136–141 (1998).

    Article  CAS  Google Scholar 

  20. Kasper, L.H. et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol. Cell. Biol. 19, 764–776 (1999).

    Article  CAS  Google Scholar 

  21. Feldmann, K.A., Pittelkow, M.R., Roche, P.C., Kumar, R. & Grande, J.P. Expression of an immediate early gene, IEX-1, in human tissues. Histochem. Cell Biol. 115, 489–497 (2001).

    CAS  PubMed  Google Scholar 

  22. Nagy, T.R. & Clair, A.L. Precision and accuracy of dual-energy X-ray absorptiometry for determining in vivo body composition of mice. Obes. Res. 8, 392–398 (2000).

    Article  CAS  Google Scholar 

  23. Tyner, S.D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

    Article  CAS  Google Scholar 

  24. Wassmann, K. & Benezra, R. Mad2 transiently associates with an APC/p55Cdc complex during mitosis. Proc. Natl. Acad. Sci. USA 95, 11193–11198 (1998).

    Article  CAS  Google Scholar 

  25. Koomen, M. et al. Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice. Hum. Mol. Genet. 11, 273–281 (2002).

    Article  CAS  Google Scholar 

  26. de Boer, J. et al. Premature aging in mice deficient in DNA repair and transcription. Science 296, 1276–1279 (2002).

    Article  CAS  Google Scholar 

  27. Woods, L.M. et al. Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice. J. Cell Biol. 145, 1395–1406 (1999).

    Article  CAS  Google Scholar 

  28. Kang-Decker, N., Mantchev, G.T., Juneja, S.C., McNiven, M.A. & van Deursen, J.M. Lack of acrosome formation in Hrb-deficient mice. Science 294, 1531–1533 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Harden, R. Babu, M. Gazi, S. Guyse, M. Pittelkow, R. Goorha, J. Davenport, D. Pearson, K. Hafner (Cytogenetics Shared Resource), J. van Ree and S. Kaufman for supporting this project; R. Bram for critically reviewing the manuscript and for discussions; and T. Yen for providing BubR1 antibody. This work was supported by a grant from the US National Institutes of Health.

Author information

Authors and Affiliations

  1. Departments of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Darren J Baker, Karthik B Jeganathan, Michael Thompson, Alena Kopecka & Jan M van Deursen

  2. Departments of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Darren J Baker, Karthik B Jeganathan, Michael Thompson, Subhash Juneja, Rajiv Kumar & Jan M van Deursen

  3. Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    J Douglas Cameron

  4. Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Rajiv Kumar & Piet C de Groen

  5. Department of Pathology, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Robert B Jenkins & Patrick Roche

Authors
  1. Darren J Baker
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Karthik B Jeganathan
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. J Douglas Cameron
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Michael Thompson
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Subhash Juneja
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Alena Kopecka
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Rajiv Kumar
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Robert B Jenkins
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Piet C de Groen
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Patrick Roche
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Jan M van Deursen
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Jan M van Deursen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Alternative RNA splicing mechanism underlying hypomorphic BubR1 expression. (PDF 108 kb)

Supplementary Fig. 2

Phenotypic analyses of Bublb+/− and Bub1bH/H mice. (PDF 1504 kb)

Supplementary Fig. 3

Analysis of spindle assembly checkpoint activity by flow cytometry. (PDF 142 kb)

Supplementary Fig. 4

Analysis of the fidelity of distinct DNA damage repair pathways by measuring cell survival and colony formation ability after exposing early-passage MEFs to various kinds of DNA damaging agents. (PDF 84 kb)

Supplementary Table 1

Summary of aging-related phenotypes. (PDF 7 kb)

Supplementary Methods

Generation of Bub1b mutant mice. (PDF 50 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baker, D., Jeganathan, K., Cameron, J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet 36, 744–749 (2004). https://doi.org/10.1038/ng1382

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1382

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