Axonal Activation of the Unfolded Protein Response Promotes Axonal Regeneration Following Peripheral Nerve Injury

Neuroscience. 2018 Apr 1;375:34-48. doi: 10.1016/j.neuroscience.2018.02.003. Epub 2018 Feb 10.


Adult mammalian peripheral neurons have an intrinsic regrowth capacity in response to axonal injury. The induction of calcium ion (Ca2+) oscillations at an injured site is critical for the regulation of regenerative responses. In polarized neurons, distal axonal segments contain a well-developed endoplasmic reticulum (ER) network that is responsible for Ca2+ homeostasis. Although these characteristics implicate the relevance among injury-induced Ca2+ dynamics, axonal ER-derived signaling, and regenerative responses propagated along the axons, the details are not fully understood. In the present study, we found that Ca2+ release from the axonal ER was accelerated in response to injury. Additionally, axonal injury-dependent Ca2+ release from the ER activated unfolded protein response (UPR) signaling at injured sites. Inhibition of axonal UPR signaling led to fragmentation of the axonal ER and disrupted growth cone formation, suggesting that activation of axonal UPR branches following axonal injury promotes regeneration via regulation of ER reconstruction and formation of growth cones. Our studies revealed that local activation of axonal UPR signaling by injury-induced Ca2+ release from the ER is critical for regeneration. These findings provide a new concept for the link between injury-induced signaling at a distant location and regulation of organelle and cytoskeletal formation in the orchestration of axonal regeneration.

Keywords: ER stress; axonal regeneration; endoplasmic reticulum (ER); growth cone; peripheral nerve injury; unfolded protein response (UPR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / pathology
  • Calcium / metabolism
  • Cations, Divalent / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress / physiology
  • Female
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism
  • Mice, Inbred ICR
  • Nerve Regeneration / physiology*
  • Peripheral Nerve Injuries / metabolism*
  • Peripheral Nerve Injuries / pathology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Sciatic Nerve / injuries
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Unfolded Protein Response / physiology*
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / metabolism


  • Cations, Divalent
  • Membrane Proteins
  • Ern2 protein, mouse
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • eIF-2 Kinase
  • Calcium