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

Abstract

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. 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, 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 of the nervous system.

Structure, function, and regulation of mitofusin‐2 in health and disease

“…Indeed, mouse and zebrafish models of CMT2A have provided crucial information on the importance of Mfn2 in normal physiology and disease (Detmer et al, 2008;Vettori et al, 2011;Chapman et al, 2013;Bannerman et al, 2016). Moreover, recent studies in small model organisms such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans have been instrumental in characterizing the role of mitochondria in neuronal health (Neumann & Hilliard, 2014;Rawson et al, 2014;Babic et al, 2015;Neumann et al, 2015;Melkov et al, 2016;Morsci et al, 2016;Yu et al, 2016). However, despite this progress, several outstanding questions and major goals for future research remain and are outlined below.…”

AFF-1 fusogen can rejuvenate the regenerative potential of adult dendritic trees via self-fusion

“…However, different invertebrates, including nematodes and crustaceans, use plasma membrane fusion as an alternative mechanism for repair of injured axons Hoy et al, 1967;Neumann et al, 2011Neumann et al, , 2015. Cell fusion events were also observed in the brains of mammals both spontaneously and as a result of injury such as stroke (Alvarez-Dolado et al, 2003;Johansson et al, 2008;Paltsyn et al, 2013), but the role of these events has remained unclear (GiordanoSantini et al, 2016).…”

“…Cell fusion events were also observed in the brains of mammals both spontaneously and as a result of injury such as stroke (Alvarez-Dolado et al, 2003;Johansson et al, 2008;Paltsyn et al, 2013), but the role of these events has remained unclear (GiordanoSantini et al, 2016). In C. elegans, axonal regeneration by autofusion is mediated by the fusogen EFF-1 Neumann et al, 2011Neumann et al, , 2015. EFF-1 is the first bona fide eukaryotic developmental cell-cell fusion protein.…”

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease

“…In vivo, Bai1 mutant mice showed defects both in normal myogenesis and in muscle regeneration after injury, suggesting an important role for apoptosis during muscle development and repair (Hochreiter-Hufford et al, 2013). Interestingly, phosphatidylserine receptor 1 (PSR-1) has recently been shown to play a crucial role in regenerative axonal fusion in C. elegans, suggesting that this mechanism of apoptosis-induced fusion is not restricted to muscle (Neumann et al, 2015).…”