Priming events and retrograde injury signals. A new perspective on the cellular and molecular biology of nerve regeneration.

Successful axon regeneration requires that signals from the site of injury reach the nucleus to elicit changes in transcription. In spite of their obvious importance, relatively few of these signals have been identified. Recent work on regeneration in the marine mollusk Aplysia californica has provided several insights into the molecular events that occur in neurons after axon injury. Based on these findings, we propose a model in which axon regeneration is viewed as the culmination of a series of temporally distinct but overlapping phases. Within each phase, specific signals enter the nucleus to prime the cell for the arrival of subsequent signals. The first phase begins with the arrival of injury-induced action potentials, which act via calcium and cAMP to turn on genes used in the early stages of repair. In the next phase, MAP-kinases and other intrinsic constituents activated at the injury site are retrogradely transported through the axon to the nucleus, informing the nucleus of the severity of the axonal injury, reinforcing the earlier events, and triggering additional changes. The third phase is characterized by the arrival of signals that originate from extrinsic growth factors and cytokines released by cells at the site of injury. In the last phase, signals from target-derived growth factors arrive in the cell soma to stop growth. Because many of these events appear to be universal, this framework may be useful in studies of nerve repair in both invertebrates and vertebrates.