Coordinated changes in the expression of Wnt pathway genes following human and rat peripheral nerve injury

PLoS One. 2021 Apr 13;16(4):e0249748. doi: 10.1371/journal.pone.0249748. eCollection 2021.


A human neuroma-in continuity (NIC), formed following a peripheral nerve lesion, impedes functional recovery. The molecular mechanisms that underlie the formation of a NIC are poorly understood. Here we show that the expression of multiple genes of the Wnt family, including Wnt5a, is changed in NIC tissue from patients that underwent reconstructive surgery. The role of Wnt ligands in NIC pathology and nerve regeneration is of interest because Wnt ligands are implicated in tissue regeneration, fibrosis, axon repulsion and guidance. The observations in NIC prompted us to investigate the expression of Wnt ligands in the injured rat sciatic nerve and in the dorsal root ganglia (DRG). In the injured nerve, four gene clusters were identified with temporal expression profiles corresponding to particular phases of the regeneration process. In the DRG up- and down regulation of certain Wnt receptors suggests that nerve injury has an impact on the responsiveness of injured sensory neurons to Wnt ligands in the nerve. Immunohistochemistry showed that Schwann cells in the NIC and in the injured nerve are the source of Wnt5a, whereas the Wnt5a receptor Ryk is expressed by axons traversing the NIC. Taken together, these observations suggest a central role for Wnt signalling in peripheral nerve regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Ganglia, Spinal / metabolism*
  • Ganglia, Spinal / pathology
  • Gene Expression Regulation
  • Humans
  • Nerve Regeneration / physiology*
  • Peripheral Nerve Injuries / genetics
  • Peripheral Nerve Injuries / metabolism*
  • Peripheral Nerve Injuries / pathology
  • Rats
  • Rats, Wistar
  • Sciatic Nerve / metabolism*
  • Sciatic Nerve / pathology
  • Sensory Receptor Cells / metabolism*
  • Sensory Receptor Cells / pathology
  • Wnt Signaling Pathway*

Grants and funding

NWO-TOP grant 91210058 ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.