Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury

J Cell Biol. 2010 Oct 4;191(1):211-23. doi: 10.1083/jcb.201006039.


Regenerative responses to axonal injury involve changes in gene expression; however, little is known about how such changes can be induced from a distant site of injury. In this study, we describe a nerve crush assay in Drosophila melanogaster to study injury signaling and regeneration mechanisms. We find that Wallenda (Wnd), a conserved mitogen-activated protein kinase (MAPK) kinase kinase homologous to dual leucine zipper kinase, functions as an upstream mediator of a cell-autonomous injury signaling cascade that involves the c-Jun NH(2)-terminal kinase MAPK and Fos transcription factor. Wnd is physically transported in axons, and axonal transport is required for the injury signaling mechanism. Wnd is regulated by a conserved E3 ubiquitin ligase, named Highwire (Hiw) in Drosophila. Injury induces a rapid increase in Wnd protein concomitantly with a decrease in Hiw protein. In hiw mutants, injury signaling is constitutively active, and neurons initiate a faster regenerative response. Our data suggest that the regulation of Wnd protein turnover by Hiw can function as a damage surveillance mechanism for responding to axonal injury.

Publication types

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

MeSH terms

  • Animals
  • Axons / physiology*
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila Proteins / physiology*
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / physiology
  • Gene Expression Regulation
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Kinase Kinases / physiology*
  • Mutation
  • Nerve Regeneration*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology
  • Neurons / cytology
  • Neurons / metabolism
  • Neurons / physiology*
  • Phosphoprotein Phosphatases / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins c-jun / metabolism
  • Proto-Oncogene Proteins c-jun / physiology
  • Signal Transduction


  • Drosophila Proteins
  • HIW protein, Drosophila
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-jun
  • kay protein, Drosophila
  • MAP Kinase Kinase Kinases
  • wnd protein, Drosophila
  • puc protein, Drosophila
  • Phosphoprotein Phosphatases