SignificanceNervous system injury can cause lifelong disability, because repair rarely leads to reconnection with the target tissue. In the nematode Caenorhabditis elegans and in several other species, regeneration can proceed through a mechanism of axonal fusion, whereby regrowing axons reconnect and fuse with their own separated fragments, rapidly and efficiently restoring the original axonal tract. We have found that the process of axonal fusion restores full function to damaged neurons. In addition, we show that injury-induced changes to the axonal membrane that result in exposure of lipid “save-me” signals mediate the level of axonal fusion. Thus, our results establish axonal fusion as a complete regenerative mechanism that can be modulated by changing the level of save-me signals exposed after injury.

Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently self-repair. This inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to patients. Compared to humans, a number of species possess far greater regenerative capabilities, and can therefore provide important insights into how our own nervous systems can be repaired. In particular, several invertebrate species have been shown to rapidly initiate regeneration post-injury, allowing separated axon segments to re-join. This process, known as axonal fusion, represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original structure. Our recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged neurons. Moreover, we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion, and discovered that the level of axonal fusion can be enhanced by promoting a neuron's intrinsic growth potential. A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting.

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