EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway

Unlike the limited post-injury neuronal regeneration in humans, severed axons in C. elegans can regenerate through a cellular fusion mechanism; this study identifies the molecular basis for this process which includes phosphatidylserine recognition and a role for specific molecules that also act in apoptosis. Axonal fusion via an engulfment-like mechanism Nerve injuries can cause life-long disabilities because neuronal repair rarely leads to re-innervation of the target tissue. A highly efficient means of regeneration occurs in the nervous system of Caenorhabditis elegans nematodes. This process, known as axonal fusion, involves a mechanism in which the re-growing axons spontaneously fuse with their own severed fragments. Massimo Hilliard and colleagues investigate the molecular machinery required for this regenerative process, and find that it begins with changes to the phospholipid composition of the axonal membrane followed by recruitment of specific molecules in the regrowing axon as well as from surrounding tissues. Remarkably, the molecules and mechanisms discovered in this process mirror those involved in the recognition and engulfment of apoptotic cells by phagocytes. Functional regeneration after nervous system injury requires transected axons to reconnect with their original target tissue. Axonal fusion, a spontaneous regenerative mechanism identified in several species, provides an efficient means of achieving target reconnection as a regrowing axon is able to contact and fuse with its own separated axon fragment, thereby re-establishing the original axonal tract 1 , 2 , 3 , 4 , 5 , 6 , 7 . Here we report a molecular characterization of this process in Caenorhabditis elegans , revealing dynamic changes in the subcellular localization of the EFF-1 fusogen after axotomy, and establishing phosphatidylserine (PS) and the PS receptor (PSR-1) as critical components for axonal fusion. PSR-1 functions cell-autonomously in the regrowing neuron and, instead of acting in its canonical signalling pathway 8 , acts in a parallel phagocytic pathway that includes the transthyretin protein TTR-52, as well as CED-7, NRF-5 and CED-6 (refs 9 , 10 , 11 , 12 ). We show that TTR-52 binds to PS exposed on the injured axon, and can restore fusion several hours after injury. We propose that PS functions as a ‘save-me’ signal for the distal fragment, allowing conserved apoptotic cell clearance molecules to function in re-establishing axonal integrity during regeneration o