The lh3 Glycosyltransferase Directs Target-Selective Peripheral Nerve Regeneration

Neuron. 2015 Nov 18;88(4):691-703. doi: 10.1016/j.neuron.2015.10.004. Epub 2015 Nov 5.

Abstract

Functional PNS regeneration requires injured axons to return to their original synaptic targets, yet the mechanisms underlying target-selective regeneration have remained elusive. Using live-cell imaging in zebrafish we find that regenerating motor axons exhibit a strong preference for their original muscle territory and that axons probe both correct and incorrect trajectories extensively before selecting their original path. We show that this process requires the glycosyltransferase lh3 and that post-injury expression of lh3 in Schwann cells is sufficient to restore target-selective regeneration. Moreover, we demonstrate that Schwann cells neighboring the transection site express the lh3 substrate collagen4a5 and that during regeneration collagen4a5 destabilizes axons probing inappropriate trajectories to ensure target-selective regeneration, possibly through the axonal repellant slit1a. Our results demonstrate that selective ECM components match subpopulations of regenerating axons with their original targets and reveal a previously unappreciated mechanism that conveys synaptic target selection to regenerating axons in vivo. VIDEO ABSTRACT.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Animals
  • Axons / physiology*
  • Collagen Type IV / genetics
  • Glycosyltransferases / genetics*
  • Motor Neurons / physiology*
  • Nerve Regeneration / genetics*
  • Nerve Tissue Proteins / metabolism
  • Peripheral Nerve Injuries
  • Peripheral Nerves / physiology*
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics*
  • Schwann Cells / metabolism*
  • Zebrafish
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism

Substances

  • Collagen Type IV
  • Nerve Tissue Proteins
  • Zebrafish Proteins
  • plod3 protein, zebrafish
  • slit1a protein, zebrafish
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • Glycosyltransferases