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¹ Department of Anatomy and Developmental Biology and ² MRC Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, London WC1E 6BT, England, UK
³ Department of Biological and Technical Research, San Raffaele Scientific Institute, 20132 Milan, Italy
⁴ Mammalian Genetics Laboratory, Cancer Research UK, London WC2A 3PX, England, UK

Correspondence to Kristján R. Jessen: k.jessen{at}ucl.ac.uk

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.

D.B. Parkinson, A. Bhaskaran, and P. Arthur-Farraj contributed equally to this paper.

D.B. Parkinson's present address is Peninsula Medical School, Tamar Science Park, Plymouth, Devon PL6 8BU, UK.

Abbreviations used in this paper: db-cAMP, dibutyryl cAMP; DM, defined medium; DRG, dorsal root ganglion; E, embryonic day; MBP, myelin basic protein; MKK7, MAPK kinase 7; NRG-1, β–neuregulin-1; P, postnatal day; P_0, protein zero.

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