Abstract
Neurofibromatosis is caused by the loss of neurofibromin (Nf1), leading to peripheral nervous system (PNS) tumors, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). A long-standing question has been whether these tumors arise from neural crest stem cells (NCSCs) or differentiated glia. Germline or conditional Nf1 deficiency caused a transient increase in NCSC frequency and self-renewal in most regions of the fetal PNS. However, Nf1-deficient NCSCs did not persist postnatally in regions of the PNS that developed tumors and could not form tumors upon transplantation into adult nerves. Adult P0a-Cre+Nf1(fl/-) mice developed neurofibromas, and Nf1(+/-)Ink4a/Arf(-/-) and Nf1/p53(+/-) mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice. Tumors appeared to arise from differentiated glia, not NCSCs.
Publication types
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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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Animals, Newborn
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Gastrointestinal Tract / drug effects
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Gastrointestinal Tract / metabolism
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Intercellular Signaling Peptides and Proteins / pharmacology
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Mice
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Mutation / genetics
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Myelin Sheath / drug effects
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Myelin Sheath / pathology
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Neoplasms / pathology*
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Nerve Sheath Neoplasms / pathology
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Neural Crest / cytology*
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Neural Crest / drug effects
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Neurofibroma, Plexiform / pathology
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Neurofibromin 1 / deficiency*
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Neuroglia / cytology
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Neuroglia / drug effects
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Peripheral Nervous System / drug effects
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Peripheral Nervous System / embryology
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Peripheral Nervous System / metabolism
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Schwann Cells / drug effects
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Schwann Cells / pathology
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Signal Transduction / drug effects
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Stem Cells / cytology*
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Stem Cells / drug effects
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Tumor Suppressor Protein p53 / metabolism
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ras Proteins / metabolism
Substances
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Intercellular Signaling Peptides and Proteins
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Neurofibromin 1
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Tumor Suppressor Protein p53
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ras Proteins