Axon plasticity in the mature nervous system can result from experience, injury, or disease. How is plasticity regulated and executed? For example, damaged axons can sometimes regenerate and recover function, but regeneration often fails and the requirements for successful regeneration are poorly understood. This lack of understanding limits development of treatments for nerve damage.

We used a genetic screen in C. elegans to find over 60 candidate genes involved in axon regeneration. Previously, we discovered that axons in mutant animals that lack beta-spectrin break spontaneously and regenerate (JCB 176(3) pp. 269-75). Because axon morphology in these mutants depends on regeneration, the mutants provide a sensitized background that enabled us to identify factors required for regeneration. Current research in the lab focuses on understanding how each of these genes contributes to the cell biology of regeneration. We have developed a suite of genetic tools to initiate and monitor regeneration. We also use femtosecond laser surgery to sever individual axons.

One example of a regeneration gene identified in the screen is the dual-leucine zipper MAP3K DLK-1. We found that DLK-1 and its downstream targets MKK-4 (MAP2K) and PMK-3 (p38 MAPK) are required for regeneration. When axons are severed in dlk-1, mkk-4, or pmk-3 mutants, the axon stump never initiates a growth cone. Importantly, these genes are not essential for axon outgrowth during development. It is only when axons are challenged to regenerate that DLK-1, MKK-4 and PMK-3 are required. Because loss of this pathway blocks regeneration at an early step (growth cone formation), DLK-1 activity appears to be a critical signal that links axon damage to initiation of regeneration.