title: 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.
authors.affiliation: CJCADR, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Brent
authors.initials: B
authors.lastname: Neumann
authors.affiliation: CJCADR, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Sean
authors.initials: S
authors.lastname: Coakley
authors.affiliation: CJCADR, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Rosina
authors.initials: R
authors.lastname: Giordano-Santini
authors.affiliation: CJCADR, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Casey
authors.initials: C
authors.lastname: Linton
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
authors.forename: Eui Seung
authors.initials: ES
authors.lastname: Lee
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Xue
authors.affiliation: CJCADR, Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Massimo A
authors.initials: MA
authors.lastname: Hilliard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009154:Mutation; D009416:Nerve Regeneration / Q000502:physiology*; D010586:Phagocytes / Q000378:metabolism; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D013049:Spectrin / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D051017:Apoptosis Regulatory Proteins; C112888:CED-6 protein, C elegans; C112887:CED-7 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C470734:EFF-1 protein, C elegans; D008562:Membrane Glycoproteins; C576460:NRF-5 protein, C elegans; D010718:Phosphatidylserines; D010750:Phosphoproteins; C479694:Psr-1 protein, C elegans; D011956:Receptors, Cell Surface; C576459:TTR-52 protein, C elegans; C408123:phosphatidylserine receptor; C409166:unc-70 protein, C elegans; D013049:Spectrin