Abstract
Hedgehog pathway activation is required for expansion of specific neuronal precursor populations during development and is etiologic in the human cerebellar tumor, medulloblastoma. We report that sonic hedgehog (Shh) signaling upregulates expression of the proto-oncogene Nmyc in cultured cerebellar granule neuron precursors (CGNPs) in the absence of new protein synthesis. The temporal-spatial expression pattern of Nmyc, but not other Myc family members, precisely coincides with regions of hedgehog proliferative activity in the developing cerebellum and is observed in medulloblastomas of Patched (Ptch) heterozygous mice. Overexpression of Nmyc promotes cell-autonomous G(1) cyclin upregulation and CGNP proliferation independent of Shh signaling. Furthermore, Myc antagonism in vitro significantly decreases proliferative effects of Shh in cultured CGNPs. Together, these findings identify Nmyc as a direct target of the Shh pathway that functions to regulate cell cycle progression in cerebellar granule neuron precursors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Cell Division / physiology
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Cells, Cultured
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Cerebellar Neoplasms / genetics
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Cerebellar Neoplasms / metabolism
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Cerebellum / cytology
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Cerebellum / embryology*
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Cerebellum / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Gene Expression Regulation, Developmental
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Hedgehog Proteins
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Heterozygote
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Intracellular Signaling Peptides and Proteins
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Medulloblastoma / genetics
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Medulloblastoma / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Neurons / drug effects
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Neurons / metabolism*
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Patched Receptors
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Patched-1 Receptor
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Receptors, Cell Surface
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Stem Cells / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Up-Regulation
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Veratrum Alkaloids / pharmacology
Substances
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Atoh1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Hedgehog Proteins
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Intracellular Signaling Peptides and Proteins
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MAS1 protein, human
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Membrane Proteins
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PTCH1 protein, human
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Patched Receptors
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Patched-1 Receptor
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-myc
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Ptch1 protein, mouse
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Receptors, Cell Surface
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Shh protein, mouse
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Trans-Activators
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Transcription Factors
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Veratrum Alkaloids
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Cyclin D1
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cyclopamine