The ubiquitin ligase PHR promotes directional regrowth of spinal zebrafish axons

Commun Biol. 2019 May 22;2:195. doi: 10.1038/s42003-019-0434-2. eCollection 2019.

Abstract

To reconnect with their synaptic targets, severed axons need to regrow robustly and directionally along the pre-lesional trajectory. While mechanisms directing axonal regrowth are poorly understood, several proteins direct developmental axon outgrowth, including the ubiquitin ligase PHR (Mycbp2). Invertebrate PHR also limits regrowth of injured axons, whereas its role in vertebrate axonal regrowth remains elusive. Here we took advantage of the high regrowth capacity of spinal zebrafish axons and observed robust and directional regrowth following laser transection of spinal Mauthner axons. We found that PHR directs regrowing axons along the pre-lesional trajectory and across the transection site. At the transection site, initial regrowth of wild-type axons was multidirectional. Over time, misdirected sprouts were corrected in a PHR-dependent manner. Ablation of cyfip2, known to promote F-actin-polymerization and pharmacological inhibition of JNK reduced misdirected regrowth of PHR-deficient axons, suggesting that PHR controls directional Mauthner axonal regrowth through cyfip2- and JNK-dependent pathways.

Keywords: Spinal cord diseases; Spinal cord injury.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alleles
  • Animals
  • Animals, Genetically Modified
  • Axons / metabolism*
  • Cadherins / metabolism
  • Cytoplasmic Dyneins / metabolism
  • Disease Models, Animal
  • Green Fluorescent Proteins / metabolism
  • Image Processing, Computer-Assisted
  • Ligases / metabolism
  • MAP Kinase Kinase 4 / metabolism
  • Mixed Function Oxygenases / metabolism*
  • Mutation
  • Nerve Regeneration*
  • Neuronal Outgrowth*
  • Spinal Cord / pathology
  • Spinal Cord Injuries / metabolism
  • Transgenes
  • Ubiquitin / metabolism
  • Zebrafish
  • Zebrafish Proteins / metabolism*

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • Cadherins
  • Celsr3 protein, zebrafish
  • Ubiquitin
  • Zebrafish Proteins
  • mycbp2 protein, zebrafish
  • Green Fluorescent Proteins
  • Mixed Function Oxygenases
  • MAP Kinase Kinase 4
  • Cytoplasmic Dyneins
  • DYNC1H1 protein, zebrafish
  • Ligases