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

Acta Neuropathol. 2012 Apr;123(4):601-14. doi: 10.1007/s00401-012-0961-0. Epub 2012 Feb 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Bacterial Proteins / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Proliferation
  • Cerebellar Neoplasms / pathology*
  • Cochlear Nucleus / pathology*
  • Eye Proteins
  • Galactosides
  • Gene Expression Profiling
  • Glial Fibrillary Acidic Protein / genetics
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Homeodomain Proteins
  • Humans
  • Indoles
  • Ki-67 Antigen / metabolism
  • Luminescent Proteins / genetics
  • Magnetic Resonance Imaging
  • Medulloblastoma / pathology*
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Phosphopyruvate Hydratase / metabolism
  • Proteins / genetics
  • RNA, Untranslated
  • Receptors, G-Protein-Coupled / genetics
  • Repressor Proteins
  • Smoothened Receptor

Substances

  • Atoh1 protein, mouse
  • Bacterial Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • Eye Proteins
  • Galactosides
  • Glial Fibrillary Acidic Protein
  • Gt(ROSA)26Sor non-coding RNA, mouse
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Indoles
  • Ki-67 Antigen
  • Luminescent Proteins
  • PAX6 Transcription Factor
  • PAX6 protein, human
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • Proteins
  • RNA, Untranslated
  • Receptors, G-Protein-Coupled
  • Repressor Proteins
  • Smo protein, mouse
  • Smoothened Receptor
  • yellow fluorescent protein, Bacteria
  • Phosphopyruvate Hydratase
  • 5-bromo-4-chloro-3-indolyl beta-galactoside