Wolfram syndrome 1b mutation suppresses Mauthner-cell axon regeneration via ER stress signal pathway

Acta Neuropathol Commun. 2022 Dec 17;10(1):184. doi: 10.1186/s40478-022-01484-8.


Wolfram Syndrome (WS) is a fatal human inherited disease with symptoms of diabetes, vision decreasing, and neurodegeneration caused by mutations in the endoplasmic reticulum (ER)-resident protein WFS1. WFS1 has been reported to play an important role in glucose metabolism. However, the role of WFS1 in axonal regeneration in the central nervous system has so far remained elusive. Herein, we established a model of the wfs1b globally deficient zebrafish line. wfs1b deficiency severely impeded the Mauthner-cell (M-cell) axon regeneration, which was partly dependent on the ER stress response. The administration of ER stress inhibitor 4-Phenylbutyric acid (4-PBA) promoted M-cell axon regeneration in wfs1b-/- zebrafish larvae, while the ER stress activator Tunicamycin (TM) inhibited M-cell axon regeneration in wfs1b+/+ zebrafish larvae. Moreover, complementation of wfs1b at the single-cell level stimulated M-cell axon regeneration in the wfs1b-/- zebrafish larvae. Altogether, our results revealed that wfs1b promotes M-cell axon regeneration through the ER stress signal pathway and provide new evidence for a therapeutic target for WS and axon degeneration.

Keywords: ER stress; Mauthner cell; Regeneration; Zebrafish; wfs1b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Endoplasmic Reticulum Stress
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mutation / genetics
  • Nerve Regeneration
  • Signal Transduction
  • Wolfram Syndrome* / genetics
  • Wolfram Syndrome* / metabolism
  • Zebrafish / metabolism


  • Membrane Proteins