RAB-5 regulates regenerative axonal fusion by controlling EFF-1 endocytosis

Following a transection injury to the axon, neurons from a number of species have the ability to undergo spontaneous repair via fusion of the two separated axonal fragments. In the nematode C. elegans, this highly efficient regenerative axonal fusion is mediated by Epithelial Fusion Failure-1 (EFF-1), a fusogenic protein that functions at the membrane to merge the two axonal fragments. Identifying modulators of axonal fusion and EFF-1 is the next step towards harnessing this process for clinical applications. Here, we present evidence that the small GTPase RAB-5 acts to inhibit axonal fusion, a function achieved via endocytosis of EFF-1 within the injured neuron. Consequently, we find that perturbing RAB-5 activity increases the capacity of the neuron to undergo axonal fusion, through enhanced membranous localization of EFF-1 and the production of extracellular EFF-1-containing vesicles. These findings identify RAB-5 as a novel regulator of axonal fusion and the first regulator of EFF-1 in neurons.