title: Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem.
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.
authors.affiliation: Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grammel
authors.forename: Monika
authors.initials: M
authors.lastname: Warmuth-Metz
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000473:pathology*; D017626:Cochlear Nucleus / Q000473:pathology*; D005136:Eye Proteins; D005697:Galactosides; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins; D006801:Humans; D007211:Indoles; D019394:Ki-67 Antigen / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D022661:RNA, Untranslated; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012097:Repressor Proteins; D000072086:Smoothened Receptor
chemical_list: D001426:Bacterial Proteins; D051792:Basic Helix-Loop-Helix Proteins; D005136:Eye Proteins; D005697:Galactosides; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D007211:Indoles; D019394:Ki-67 Antigen; D008164:Luminescent Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010751:Phosphopyruvate Hydratase; D011506:Proteins; D022661:RNA, Untranslated; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; D000072086:Smoothened Receptor; C500943:Atoh1 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C000605730:PAX6 protein, human; C000605732:Pax6 protein, mouse; C491022:Smo protein, mouse; C054562:yellow fluorescent protein, Bacteria; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside