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.
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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.
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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)
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Includes figure legends and supplementary methods (PDF 33 kb)
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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
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DOI: https://doi.org/10.1038/nature02385
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