Axon regeneration following nerve injury is a highly conserved process in animals. The nematode Caenorhabditis elegans is an excellent model for investigating the molecular mechanisms of axon regeneration. Recent studies using C. elegans have shown that the c-Jun N-terminal kinase (JNK) plays the important role in axon regeneration. Furthermore, many factors have been identified that act upstream of the JNK cascade after axotomy. This review introduces these factors and describes their roles during the regulation of axon regeneration.

Most neurons have long processes called axons, which send signals to adjacent neurons or muscles. A cut in the axon, due to trauma or surgery, impairs the neuronal function. In particular, axon injuries in the CNS, comprising the spinal cord and brain, are not efficiently repaired and frequently give rise to irreversible locomotor, sensory and cognitive disorders (1). In contrast to the CNS, neurons of the PNS can regenerate their axons by a process called axon regeneration (2). In the PNS, the distal fragment of the axon separated from the cell body by injury degenerates and eventually disappears. However, the proximal region of the axon connected to the cell body forms a growth cone at the tip and begins to re-grow towards the target to rebuild the neural circuit. Previous studies using mammalian cell culture system have suggested the involvement of many signalling factors like calcium (Ca2+) influx, elevation in cyclic AMP (cAMP) levels, growth factors, protein kinases and transcription factors, in axon regeneration (2). However, results obtained with cultured cells often do not reflect results from in vivo studies, and additional experiments in whole animals are required for studying axon regeneration. Despite this need, experiments with mammals are not easy because of the relatively difficult surgical techniques and methods of evaluation, and they also require considerable labour and time.

Our studies based on svh genes have identified many factors regulating axon regeneration through the JNK MAPK cascade and provided new insights into the mechanisms of axon regeneration. Nevertheless, our knowledge is still insufficient for understanding the whole mechanism initiating regrowth and re-creation of functional neurons. In particular, the downstream factors of the JNK MAPK cascade in axon regeneration are poorly understood, with the exception of fos-1. Since many svh genes have not yet been investigated, further analysis of these genes will be a breakthrough to discover downstream factors of JNK and to understand the entire signalling network regulating axon regeneration.

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