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:

Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas

Nature volume 428, pages 337–341 (2004)Cite this article

Abstract

Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors1,2. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated1,3. Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to medulloblastoma development4. We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, these findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for Bmi1-containing polycomb complexes in proliferation of cerebellar precursor cells.

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: Bmi1 expression in cerebellar precursor cells during development.
Figure 2: Cerebellar phenotype of Bmi1-/- mice and analysis of proliferation and apoptosis.
Figure 3: Bmi1 is essential for efficient CGC proliferation on Shh treatment.
Figure 4: Overexpression of BMI1 in 67% of analysed medulloblastomas correlates with SHH pathway activation.

Similar content being viewed by others

References

  1. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678–2690 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. van der Lugt, N. M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994)

    Article  CAS  PubMed  Google Scholar 

  4. Dahmane, N. & Ruiz-i-Altaba, A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126, 3089–3100 (1999)

    PubMed  Google Scholar 

  5. Kenney, A. M., Cole, M. D. & Rowitch, D. H. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130, 15–28 (2003)

    Article  CAS  PubMed  Google Scholar 

  6. Knoepfler, P. S., Cheng, P. F. & Eisenman, R. N. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 16, 2699–2712 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Huard, J. M., Forster, C. C., Carter, M. L., Sicinski, P. & Ross, M. E. Cerebellar histogenesis is disturbed in mice lacking cyclin D2. Development 126, 1927–1935 (1999)

    CAS  PubMed  Google Scholar 

  8. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Molofsky, A. V. et al. Bmi1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wechsler-Reya, R. J. & Scott, M. P. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22, 103–114 (1999)

    Article  CAS  PubMed  Google Scholar 

  12. Rubin, J. B. & Rowitch, D. H. Medulloblastoma: a problem of developmental biology. Cancer Cell 2, 7–8 (2002)

    Article  CAS  PubMed  Google Scholar 

  13. Zurawel, R. H. et al. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosom. Cancer 27, 44–51 (2000)

    Article  CAS  PubMed  Google Scholar 

  14. Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24, 385–428 (2001)

    Article  CAS  PubMed  Google Scholar 

  15. Taylor, M. D. et al. Mutations in SUFU predispose to medulloblastoma. Nature Genet. 31, 306–310 (2002)

    Article  CAS  PubMed  Google Scholar 

  16. Dong, J., Gailani, M. R., Pomeroy, S. L., Reardon, D. & Bale, A. E. Identification of PATCHED mutations in medulloblastomas by direct sequencing. Hum. Mutat. 16, 89–90 (2000)

    Article  CAS  PubMed  Google Scholar 

  17. Pietsch, T. et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 57, 2085–2088 (1997)

    CAS  PubMed  Google Scholar 

  18. Pomeroy, S. L. et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415, 436–442 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Herms, J. et al. C-MYC expression in medulloblastoma and its prognostic value. Int. J. Cancer 89, 395–402 (2000)

    Article  CAS  PubMed  Google Scholar 

  20. Tomlinson, F. H. et al. Aggressive medulloblastoma with high-level N-myc amplification. Mayo Clin. Proc. 69, 359–365 (1994)

    Article  CAS  PubMed  Google Scholar 

  21. Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee, Y. et al. A molecular fingerprint for medulloblastoma. Cancer Res. 63, 5428–5437 (2003)

    CAS  PubMed  Google Scholar 

  23. Smith, K. S. et al. Bmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1. Mol. Cell 12, 393–400 (2003)

    Article  CAS  PubMed  Google Scholar 

  24. Ruppert, J. M., Vogelstein, B. & Kinzler, K. W. The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A. Mol. Cell. Biol. 11, 1724–1728 (1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Miyoshi, H., Blomer, U., Takahashi, M., Gage, F. H. & Verma, I. M. Development of a self-inactivating lentivirus vector. J. Virol. 72, 8150–8157 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank P. Kleihues and H. Ohgaki for providing medulloblastoma samples; M. Grotzer for medulloblastoma cell lines; E. R. Fearon for RK3E cells; M. Ruppert for Gli cDNAs; D. Trono for the lentivirus Bmi1 construct; I. Camenisch for technical help; and K. Kieboom for animal care. MATH-1 and mGluR-2 probes were gifts from H. Zoghbi and S. Nakanishi, respectively. We thank A. Lund, M. Hernandez and S. Bruggeman for discussions, and P. U. Heitz for support. This work was supported by grants from the ‘Krebsforschung Schweiz’ to S.M. and from the ‘Novartis Stiftung’ to S.M.; M. L. and E. T. were supported by a Pioneer grant from the Netherlands organization for Scientific Research to M.v.L.

Author information

Author notes

  1. Carly Leung and Merel Lingbeek: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Clinical Pathology, Department of Pathology, University of Zürich, Schmelzbergstrasse 12, 8091, Zürich, Switzerland

    Carly Leung, Olga Shakhova, James Liu, Parvin Saremaslani & Silvia Marino

  2. Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Merel Lingbeek, Ellen Tanger & Maarten van Lohuizen

Authors
  1. Carly Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Merel Lingbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olga Shakhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ellen Tanger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Parvin Saremaslani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maarten van Lohuizen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Silvia Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Maarten van Lohuizen or Silvia Marino.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Immunohistochemical detection of Bmi1 expression in neural progenitors of the developing EGL and NE at E14.5 in the mouse (middle). No expression in E14.5 Bmi1-/- embryos (left). Note the similar Bmi1 expression in the EGL of a 17.GW human embryo (right). (PDF 146 kb)

Supplementary Figure 2

Lack of Bmi1 overexpression in 7 glioblastomas (number 1 to 7, A=normal adult cerebellum and M=medulloblastoma). (PDF 42 kb)

Supplementary Information

Includes figure legends and supplementary methods (PDF 33 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leung, C., Lingbeek, M., Shakhova, O. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004). https://doi.org/10.1038/nature02385

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02385

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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