Acta Neuropathologica

, Volume 123, Issue 4, pp 601–614

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


  • Daniel Grammel
    • Center for NeuropathologyLudwig-Maximilians-University
  • Monika Warmuth-Metz
    • Department of NeuroradiologyUniversity of Würzburg
  • André O. von Bueren
    • Department of Pediatric Hematology and OncologyUniversity Medical Center Hamburg-Eppendorf
  • Marcel Kool
    • Division of Molecular GeneticsGerman Cancer Research Center
  • Torsten Pietsch
    • Institute of Neuropathology, University of Bonn
  • Hans A. Kretzschmar
    • Center for NeuropathologyLudwig-Maximilians-University
  • David H. Rowitch
    • Eli and Edythe Broad Institute of Regeneration Medicine and Stem Cell Research and Howard Hughes Medical Institute, University of California San Francisco
    • Department of PediatricsUniversity of California San Francisco
  • Stefan Rutkowski
    • Department of Pediatric Hematology and OncologyUniversity Medical Center Hamburg-Eppendorf
  • Stefan M. Pfister
    • Division of Molecular GeneticsGerman Cancer Research Center
    • Department of Pediatric Oncology, Hematology and ImmunologyUniversity of Heidelberg
    • Center for NeuropathologyLudwig-Maximilians-University
Original Paper

DOI: 10.1007/s00401-012-0961-0

Cite this article as:
Grammel, D., Warmuth-Metz, M., von Bueren, A.O. et al. Acta Neuropathol (2012) 123: 601. doi:10.1007/s00401-012-0961-0


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.


MedulloblastomaSonic hedgehogOriginBrainstemCochlear nuclei

Supplementary material

401_2012_961_MOESM1_ESM.ppt (153 kb)
Supplementary material 1 (PPT 153 kb)
401_2012_961_MOESM2_ESM.doc (116 kb)
Supplementary material 2 (DOC 115 kb)
401_2012_961_MOESM3_ESM.xlsx (24 kb)
Supplementary material 3 (XLSX 24 kb)

Copyright information

© Springer-Verlag 2012