Understanding how neurons regenerate is an important key to treating neuronal damage due to injury or disease. How do neurons recognize breaks and how do they regulate and execute regrowth? This has been an active area of research for over 100 years and yet we still do not have a comprehensive molecular model, nor is there an effective treatment for axotomy. To gain insight into the molecular requirements for regeneration we completed an RNAi screen for genes required for axon regeneration. From this screen we identified the MAPKKK DLK-1 (1). Nervous system development and behavior are normal in
dlk-1 mutants. However, the GABA motor neurons never regenerate following laser axotomy in an otherwise wild-type background. By contrast, 70% of wild-type L4 GABA neurons are capable of regeneration. DLK-1 is part of a signaling cascade that includes the downstream MAPKK MKK-4 and the
p38 MAPK PMK-3. Mutants in either downstream gene also fail to regenerate after surgery. Furthermore, overexpression of
dlk-1 improves regeneration. New growth gone initiation occurs much sooner and appear more like embryonic growth cones in morphology, behavior, and successful migration to target sites. Thus, activation of DLK-1 promotes neuronal regrowth. Recently we have shown that a second MAPK cascade is also essential for regeneration. Mutations in the MAPKKK gene
mlk-1, the MAPKK
mek-1, and the Jnk-like MAPK
kgb-1 block regeneration, while overexpression of
mlk-1 improves regeneration. Analysis of double mutants between the
dlk-1 and
mlk-1 pathways reveals cross-talk at each of the steps. We have also shown that the dual-specificity phosphatase VHP-1 genetically and biochemically interacts with PMK-3 and KGB-1 to inhibit both pathways. The layers of complexity increase with the addition of two MAPKs acting as strong negative regulators of regeneration. Mutations in the Jnk-like MAPKs
jnk-1 and
kgb-2 result in improved regeneration while overexpression of each blocks regeneration. This overexpression effect requires kinase activity suggesting that multiple MAPK pathways function antagonistically to control regeneration. The coordinated regulation of these positive and negative signals is likely to preserve the balance between maintaining a fixed nervous system and allowing for plasticity under certain conditions such as injury or disease. (1) Hammarlund et al. 2009 Science 323: 802.