Abstract
Schwann cell myelination depends on Krox-20/Egr2 and other promyelin transcription factors that are activated by axonal signals and control the generation of myelin-forming cells. Myelin-forming cells remain remarkably plastic and can revert to the immature phenotype, a process which is seen in injured nerves and demyelinating neuropathies. We report that c-Jun is an important regulator of this plasticity. At physiological levels, c-Jun inhibits myelin gene activation by Krox-20 or cyclic adenosine monophosphate. c-Jun also drives myelinating cells back to the immature state in transected nerves in vivo. Enforced c-Jun expression inhibits myelination in cocultures. Furthermore, c-Jun and Krox-20 show a cross-antagonistic functional relationship. c-Jun therefore negatively regulates the myelinating Schwann cell phenotype, representing a signal that functionally stands in opposition to the promyelin transcription factors. Negative regulation of myelination is likely to have significant implications for three areas of Schwann cell biology: the molecular analysis of plasticity, demyelinating pathologies, and the response of peripheral nerves to injury.
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 Dedifferentiation / drug effects
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Coculture Techniques
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Cyclic AMP / pharmacology
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Early Growth Response Protein 2 / metabolism
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Ganglia, Spinal / metabolism
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Ganglia, Spinal / pathology
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HMGB Proteins / metabolism
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MAP Kinase Kinase 7 / metabolism
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Mice
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Myelin Proteins / metabolism
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Myelin Sheath / metabolism*
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Myelin Sheath / pathology
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Octamer Transcription Factor-6 / metabolism
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism*
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Rats
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SOXB1 Transcription Factors
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Schwann Cells / drug effects
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Schwann Cells / enzymology
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Schwann Cells / pathology
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Transcription Factors / metabolism
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Up-Regulation / drug effects
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Wallerian Degeneration / pathology
Substances
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DNA-Binding Proteins
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Early Growth Response Protein 2
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HMGB Proteins
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Myelin Proteins
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Proto-Oncogene Proteins c-jun
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SOXB1 Transcription Factors
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Sox2 protein, mouse
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Sox2 protein, rat
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Transcription Factors
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Octamer Transcription Factor-6
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Cyclic AMP
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MAP Kinase Kinase 7