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Published 2 February 2004. doi:10.1083/jcb.200307132
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 3, 385-394
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Article

 Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death

David B. Parkinson, Ambily Bhaskaran, Anna Droggiti, Sarah Dickinson, Maurizio D'Antonio, Rhona Mirsky, and Kristjan R. Jessen

Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, UK

Address correspondence to David B. Parkinson, Department of Anatomy and Developmental Biology, University College London, Gower Street, London, WC1E 6BT UK. Tel.: 44-20-7679-3365. Fax: 44-20-7679-2091. email: david.parkinson{at}ucl.ac.uk

The transcription factor Krox-20 controls Schwann cell myelination. Schwann cells in Krox-20 null mice fail to myelinate, and unlike myelinating Schwann cells, continue to proliferate and are susceptible to death. We find that enforced Krox-20 expression in Schwann cells cell-autonomously inactivates the proliferative response of Schwann cells to the major axonal mitogen ß–neuregulin-1 and the death response to TGFß or serum deprivation. Even in 3T3 fibroblasts, Krox-20 not only blocks proliferation and death but also activates the myelin genes periaxin and protein zero, showing properties in common with master regulatory genes in other cell types. Significantly, a major function of Krox-20 is to suppress the c-Jun NH2-terminal protein kinase (JNK)–c-Jun pathway, activation of which is required for both proliferation and death. Thus, Krox-20 can coordinately control suppression of mitogenic and death responses. Krox-20 also up-regulates the scaffold protein JNK-interacting protein 1 (JIP-1). We propose this as a possible component of the mechanism by which Krox-20 regulates JNK activity during Schwann cell development.

Key Words: egr2; JIP-1; neuregulin; PNS; myelin

Abbreviations used in this paper: DM, defined medium; JBD, JNK binding domain; JIP-1, JNK-interacting protein 1; JNK, c-Jun NH2-terminal protein kinase; NRG-1, ß-neuregulin-1; P0, protein zero.


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