JNK/c-Jun Signaling and Peripheral Nerve Regeneration

Abstract: The events associated with axonal injury in the peripheral nervous system (PNS) have been described in detail. However, the molecular mechanisms underlying the regenerative response, or neuronal cell death, following axonal injury are poorly understood. This thesis concerns one such molecular mechanism, JNK-mediated c-Jun activation, in peripheral sensory and sympathetic neurons. By immunohistochemistry, we demonstrate that the transcription factor c-Jun is rapidly activated by the mitogen activated protein kinase (MAPK) JNK, in both sensory and sympathetic neurons after axonal injury. Prevention of c-Jun activation with JNK inhibitors revealed that this activation is associated with survival and axonal outgrowth of developing sensory and sympathetic neurons. In adult sensory neurons, c-Jun activation is not required for survival, although it is required for axonal outgrowth. Additionally, c-Jun forms dimers with other transcription factors and it is plausible that the expression of these dimerization partners could regulate the physiological effect of c-Jun activation. We found that the activating transcription factor 3 (ATF3) was induced upon axonal injury in sensory and sympathetic neurons and that it colocalized with activated c-Jun. Consequently, we speculate that c-Jun/ATF3 dimers could be important for the regenerative response of peripheral neurons. Such dimers could promote a survival response in neurons under stress situations by inducing the expression of anti-apoptotic proteins such as heat shock protein 27 (Hsp27). We also made attempts to unravel the mechanism by which information of a distal axonal injury is conveyed to the cell body. We demonstrate that components of the JNK signaling pathway are axonally transported from the injury site to the cell body of dorsal root ganglia (DRG) sensory neurons, and also that this transport may contribute to the nuclear increase in c-Jun activity. Hence, we suggest that axonal transport of JNK signaling components could be involved in the transmission of injury information. Furthermore, since c-Jun activation may depend on deprivation of target-derived trophic factors, which is one consequence of axotomy, we analyzed the effect of nerve growth factor (NGF) on c-Jun activation in sensory and sympathetic neurons. NGF did not affect c-Jun activation in embryonic and adult sensory neurons, but it did affect c-Jun activation in neonatal sensory and sympathetic neurons. In conclusion, c-Jun activation seems to be a general neuronal response to peripheral nerve injury, and this response is associated with survival and regeneration.