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

Nature. 2015 Jan 8;517(7533):219-22. doi: 10.1038/nature14102.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Axons / metabolism*
  • Axons / pathology
  • Caenorhabditis elegans / cytology*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / metabolism
  • Growth Cones / metabolism
  • Membrane Glycoproteins / metabolism*
  • Mutation
  • Nerve Regeneration / physiology*
  • Phagocytes / metabolism
  • Phagocytosis
  • Phosphatidylserines / metabolism
  • Phosphoproteins / metabolism
  • Receptors, Cell Surface / metabolism
  • Signal Transduction
  • Spectrin / genetics
  • Spectrin / metabolism


  • ATP-Binding Cassette Transporters
  • Apoptosis Regulatory Proteins
  • CED-6 protein, C elegans
  • CED-7 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • EFF-1 protein, C elegans
  • Membrane Glycoproteins
  • NRF-5 protein, C elegans
  • Phosphatidylserines
  • Phosphoproteins
  • Psr-1 protein, C elegans
  • Receptors, Cell Surface
  • TTR-52 protein, C elegans
  • phosphatidylserine receptor
  • unc-70 protein, C elegans
  • Spectrin