The ability to stimulate functional neuronal regeneration would markedly enhance treatment of brain injuries and neurodegenerative diseases. In studies of C. elegans, Pinan-Lucarre et al. uncovered unexpected roles for apoptotic proteins in promoting neuronal regeneration that might be conserved across species. Worms mutant for CED-3, the core executioner apoptotic protease in C. elegans, had slower axonal outgrowth and delayed neuronal reconnections after laser-mediated injury. The CED-3-activating protein CED-4 [homologue of mammalian apoptosis protease activating factor-1 (Apaf-1)], but not other upstream apoptotic proteins, was also important. They also linked CED-3 and CED-4 to a pathway involving DLK-1, a kinase implicated in regeneration across species. Finally, they showed that this regenerative pathway involves Ca2+ signalling (known to be important in neuronal responses to injury) and specifically the conserved Ca2+-binding protein calreticulin. The authors propose a model whereby injury-induced Ca2+ signalling amplified by calreticulin promotes CED-4-mediated activation of CED-3, which then acts upstream of a DLK-1-mediated regenerative pathway. These data uncover a previously unknown pathway that will guide future studies of neuronal regeneration in higher organisms.

Pinan-LucarreB., GabelC. V., ReinaC. P., HulmeS. E., ShevkoplyasS. S., SloneR. D., XueJ., QiaoY., WeisbergS., RoodhouseK., et al.  (2012). The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in Caenorhabditis elegans. PLoS Biol.10, e1001331. doi: https://doi.org/10.1371/journal.pbio.1001331.

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