c-Jun is a negative regulator of myelination.
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.
Parkinson
David B
DB
Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, England, UK.
Bhaskaran
Ambily
A
Arthur-Farraj
Peter
P
Noon
Luke A
LA
Woodhoo
Ashwin
A
Lloyd
Alison C
AC
Feltri
M Laura
ML
Wrabetz
Lawrence
L
Behrens
Axel
A
Mirsky
Rhona
R
Jessen
Kristján R
KR
D000818:Animals; D000831:Animals, Newborn; D054337:Cell Dedifferentiation / Q000187:drug effects; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D024002:HMGB Proteins / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D051379:Mice; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D050816:Octamer Transcription Factor-6 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D055748:SOXB1 Transcription Factors; D012583:Schwann Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014855:Wallerian Degeneration / Q000473:pathology
D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; D024002:HMGB Proteins; D009185:Myelin Proteins; D016755:Proto-Oncogene Proteins c-jun; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C527784:Sox2 protein, rat; D014157:Transcription Factors; D050816:Octamer Transcription Factor-6; D000242:Cyclic AMP; D048688:MAP Kinase Kinase 7