Robo2 drives target-selective peripheral nerve regeneration in response to glia-derived signals

Murphy, P.L., Isaacman-Beck, J., Granato, M.
The Journal of neuroscience : the official journal of the Society for Neuroscience   42(5): 762-776 (Journal)
Registered Authors
Granato, Michael
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Axons/chemistry
  • Axons/physiology*
  • Motor Neurons/chemistry
  • Motor Neurons/physiology
  • Nerve Regeneration/physiology*
  • Neuroglia/chemistry
  • Neuroglia/physiology*
  • Peripheral Nerves/chemistry
  • Peripheral Nerves/physiology*
  • Receptors, Immunologic/analysis
  • Receptors, Immunologic/genetics*
  • Receptors, Immunologic/metabolism*
  • Zebrafish
  • Zebrafish Proteins/analysis
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism*
34916258 Full text @ J. Neurosci.
Peripheral nerves are divided into multiple branches leading to divergent synaptic targets. This poses a remarkable challenge for regenerating axons as they select their original trajectory at nerve branch-points. Despite implications for functional regeneration, the molecular mechanisms underlying target selectivity are not well characterized. Danio Rerio (zebrafish) motor nerves are composed of a ventral and a dorsal branch that diverge at a choice-point, and we have previously shown that regenerating axons faithfully select their original branch and targets. Here we identify Robo2 as a key regulator of target-selective regeneration (sex of experimental subjects unknown). We demonstrate that Robo2 function in regenerating axons is required and sufficient to drive target-selective regeneration, and that Robo2 acts in response to glia located precisely where regenerating axons select the branch-specific trajectory to prevent and correct axonal errors. Combined our results reveal a glia derived mechanism that acts locally via axonal Robo2 to promote target-selective regeneration.SIGNIFICANCE STATEMENT:Despite its relevance for functional recovery, the molecular mechanisms that direct regenerating peripheral nerve axons towards their original targets are not well defined. Zebrafish spinal motor nerves are composed of a dorsal and a ventral branch that diverge at a stereotyped nerve branch-point, providing a unique opportunity to decipher the molecular mechanisms critical for target-selective regeneration. Using a combination of live cell imaging and molecular-genetic manipulations we demonstrate that the robo2 guidance receptor is necessary and sufficient to promote target-selective regeneration. Moreover, we demonstrate that Robo2 is part of a genetic pathway that generates transient, spatially restricted, and tightly coordinated signaling events that direct axons of the dorsal nerve branch towards their original, pre-injury targets.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes