JNK3 contributes to c-Jun activation and apoptosis but not oxidative stress in nerve growth factor-deprived sympathetic neurons

The stress activated protein kinase pathway culminates in c-Jun phosphoryla tion mediated by the Jun Kinases (JNKs). The role of the JNK pathway in sym pathetic neuronal death is unclear in that apoptosis is not inhibited by a dominant negative protein of one JNK kinase, SEK1, but is inhibited by CEP- 1347, a compound known to inhibit this overall pathway but not JNKs per se. To evaluate directly the apoptotic role of the JNK isoform that is selecti vely expressed in neurons, JNK3, we isolated sympathetic neurons from JNK3- deficient mice and quantified nerve growth factor (NGF) deprivation-induced neuronal death, oxidative stress, c-Jun phosphorylation, and c-jun inducti on. Here, we report that oxidative stress in neurons from JNK3-deficient mi ce is normal after NGF deprivation. In contrast, NGF-deprivation-induced in creases in the levels of phosphorylated c-jun, c-jun, and apoptosis are eac h inhibited in JNK3-deficient mice, Overall, these results indicate that JN K3 plays a critical role in activation of c-Jun and apoptosis in a classic model of cell-autonomous programmed neuron death.