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Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem

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Abstract

Medulloblastoma is a malignant brain tumor of childhood that comprises at least four molecularly distinct subgroups. We have previously described that cerebellar granule neuron precursors may give rise to the subgroup with a molecular fingerprint of Sonic hedgehog (Shh) signaling. Other recent data indicate that precursor cells within the dorsal brain stem may serve as cellular origins for Wnt-associated medulloblastomas. To see whether Shh-associated medulloblastomas are also able to develop in the dorsal brainstem, we analyzed two lines of transgenic mice with constitutive Shh signaling in hGFAP- and Math1-positive brainstem precursor populations, respectively. Our results show that in both of these lines, medulloblastomas arise from granule neuron precursors of the cochlear nuclei, a derivative of the auditory lower rhombic lip. This region is distinct from derivatives of precerebellar lower rhombic lip where medulloblastomas arise in mice with constitutive-active Wnt signaling. With respect to their histology and the expression of appropriate markers, Shh tumors from the murine cochlear nuclei perfectly resemble human Shh-associated medulloblastomas. Moreover, we find that in a series of 63 human desmoplastic medulloblastomas, 21 (33%) have a very close contact to the cochlear nuclei on MR imaging. In conclusion, we demonstrate that precursors of the murine rhombic lip, which either develop into cerebellar or into cochlear granule neurons, may give rise to Shh-associated medulloblastoma, and this has important implications for the cellular origin of human medulloblastomas.

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Acknowledgments

We are indebted to Severin Filser, Michael Schmidt, Veronika Kaltenbrunn and Silvia Occhionero for excellent technical support as well as to Dr. Mehdi Shakarami and Julia Geyer for animal husbandry. We thank Dr. R. Segal (Harvard University, Boston, MA) for providing the anti-Zic1 antibody and ptch1 +/− brains. We also thank Peter van Sluis, Jan Koster, and Richard Volckmann (Academic Medical Center Amsterdam) for help with expression profiling. This work was supported by grants from the German Cancer Aid (Max-Eder-junior-research-program), the Fritz-Thyssen-Stiftung and the Förderprogramm für Forschung und Lehre (FöFoLe) at the Ludwig-Maximilians-University (all to US). M.K. is supported by Koningin Wilhelmina Fonds (grant no UvA-2011-4713) and KIKA. The HIT-trial-office at the University Medical Center Hamburg-Eppendorf is supported by the German Children’s Cancer Foundation (Deutsche Kinderkrebsstiftung) and by the Fördergemeinschaft Kinderkrebszentrum Hamburg e. V.

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Authors and Affiliations

  1. Center for Neuropathology, Ludwig-Maximilians-University, Feodor-Lynen-Strasse 23, 81377, Munich, Germany

    Daniel Grammel, Hans A. Kretzschmar & Ulrich Schüller

  2. Department of Neuroradiology, University of Würzburg, Würzburg, Germany

    Monika Warmuth-Metz

  3. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    André O. von Bueren & Stefan Rutkowski

  4. Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany

    Marcel Kool & Stefan M. Pfister

  5. Institute of Neuropathology, University of Bonn, Bonn, Germany

    Torsten Pietsch

  6. Eli and Edythe Broad Institute of Regeneration Medicine and Stem Cell Research and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA

    David H. Rowitch

  7. Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

    David H. Rowitch

  8. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany

    Stefan M. Pfister

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  1. Daniel Grammel
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  2. Monika Warmuth-Metz
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  3. André O. von Bueren
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  10. Ulrich Schüller
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Correspondence to Ulrich Schüller.

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Grammel, D., Warmuth-Metz, M., von Bueren, A.O. et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol 123, 601–614 (2012). https://doi.org/10.1007/s00401-012-0961-0

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  • DOI: https://doi.org/10.1007/s00401-012-0961-0

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