Neuronal repair: Apoptotic proteins make good

The potential of the central nervous system (CNS) to regenerate is regulated by a complex interaction of neuronal intrinsic and extrinsic factors that remain poorly understood. Significant research has been dedicated to identifying these factors to facilitate design of therapies that will treat the functional impairment associated with CNS injuries. Over the last decade, the development of in vivo laser severing of single axons in C. elegans has established an invaluable model for the genetic identification of novel regeneration factors. In a recent study we report the unexpected identification of the core apoptotic proteins CED-4/Apaf-1 and the executioner caspase CED-3 as important factors that promote early events in regeneration in C. elegans. Other upstream regulators of apoptosis do not influence regeneration, indicating the existence of a novel mechanism for activation of CED-4 and CED-3 in neuronal repair. CED-4 and CED-3 function downstream of injury-induced calcium transients and appear to act through the conserved DLK-1 pathway to promote regeneration. We propose a working model for calcium-dependent localized activation of CED-4 and CED-3 caspase and discuss questions raised including mechanisms for spatially regulating activated CED-3 and the possible substrates that it might cleave to initiate regeneration.