Abstract
The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers / metabolism
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Brain Stem / embryology
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Brain Stem / metabolism
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Cell Differentiation
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Cell Lineage*
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Cerebellar Neoplasms / metabolism
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Cerebellar Neoplasms / pathology
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Cerebellum / embryology
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Cerebellum / metabolism
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Female
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Gestational Age
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Glioma / metabolism
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Glioma / pathology
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism
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Humans
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Kruppel-Like Transcription Factors / metabolism
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Medulloblastoma / metabolism
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Medulloblastoma / pathology
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Mice
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Mice, Nude
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Mice, Transgenic
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Mutation
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N-Myc Proto-Oncogene Protein
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Neural Stem Cells / metabolism*
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Neural Stem Cells / pathology
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Neuroectodermal Tumors, Primitive / metabolism
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Neuroectodermal Tumors, Primitive / pathology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Prosencephalon / embryology
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Prosencephalon / metabolism
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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SOX9 Transcription Factor / genetics
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SOX9 Transcription Factor / metabolism
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Signal Transduction
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Spheroids, Cellular
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Time Factors
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Transduction, Genetic
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Zinc Finger Protein Gli2
Substances
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Biomarkers
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Gli2 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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MAS1 protein, human
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MYCN protein, human
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MYCN protein, mouse
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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SHH protein, human
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SOX9 Transcription Factor
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SOX9 protein, human
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Shh protein, mouse
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Sox9 protein, mouse
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Zinc Finger Protein Gli2