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J. Biol. Chem., Vol. 280, Issue 2, 1132-1141, January 14, 2005

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c-Jun N-terminal Kinase 3 Deficiency Protects Neurons from Axotomy-induced Death in Vivo through Mechanisms Independent of c-Jun Phosphorylation^*

Elizabeth Keramaris, Jacqueline L. Vanderluit, Mohammad Bahadori, Kambiz Mousavi, Roger J. Davis¶, Richard Flavell||, Ruth S. Slack, and David S. Park**

From the Neuroscience East, Ottawa Health Research Institute and the Department of Cellular Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the ^¶Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and the ^||Section of Immunobiology, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, Connecticut 06520

Both the transcription factor c-Jun and the c-Jun N-terminal kinases (JNKs) have been associated with neuronal loss in several death paradigms. JNK are key regulators of c-Jun and a common accepted model has been that JNKs mediate neuronal death through modulation of c-Jun activation. In the present study, we examined whether JNK2 and -3 (JNK members most associated with neuronal loss) deficiency can rescue neuronal loss caused by facial and sciatic nerve axotomy in the neonate in vivo. JNK2, JNK3, and JNK2/3 double-deficient neurons displayed significantly less death in the facial nerves of the CNS when compared with controls. JNK2 and JNK2/3 double-deficient animals also showed reduced c-Jun phosphorylation and induction following axotomy, consistent with the model that JNK acts to regulate death by activating c-Jun. Of significance, however, protection of facial nerves in JNK3-deficient animals was not accompanied by reduction in c-Jun activation. These results suggest that JNKs can mediate death independently of c-Jun. Importantly, the lack of correlation between JNK3 deficiency and c-Jun induction was not universal. In a sciatic axotomy model of neuronal injury in the neonate, death of DRG neurons was also reduced by JNK3 deficiency. However, in this case, c-Jun activation was also eliminated.

Received for publication, September 2, 2004 , and in revised form, October 22, 2004.

^* This work was supported by the Canadian Stroke Network and Canadian Institute of Health Research (to D. S. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 613-562-5800 (ext. 8816); Fax: 613-562-5403; E-mail: dpark{at}uottawa.ca.

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