c-Jun N-terminal kinase 3 deficiency protects neurons from axotomy-induced death in vivo through mechanisms independent of c-Jun phosphorylation.
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.
Keramaris
Elizabeth
E
Neuroscience East, Ottawa Health Research Institute, Ontario, Canada.
Vanderluit
Jacqueline L
JL
Bahadori
Mohammad
M
Mousavi
Kambiz
K
Davis
Roger J
RJ
Flavell
Richard
R
Slack
Ruth S
RS
Park
David S
DS
D000818:Animals; D019771:Axotomy; D016923:Cell Death; D005145:Face / Q000294:innervation; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D048057:Mitogen-Activated Protein Kinase 10 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012584:Sciatic Nerve / Q000502:physiology / Q000601:surgery
D016755:Proto-Oncogene Proteins c-jun; D010768:Phosphoserine; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9