Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury

Nat Neurosci. 2012 Mar 18;15(5):722-30. doi: 10.1038/nn.3066.

Abstract

Neuronal injury elicits potent cellular responses from glia, but molecular pathways modulating glial activation, phagocytic function and termination of reactive responses remain poorly defined. Here we show that positive or negative regulation of glial responses to axon injury is molecularly encoded by unique isoforms of the Drosophila melanogaster engulfment receptor Draper. Draper-I promotes engulfment of axonal debris through an immunoreceptor tyrosine-based activation motif (ITAM). In contrast, Draper-II, an alternative splice variant, potently inhibits glial engulfment function. Draper-II suppresses Draper-I signaling through a previously undescribed immunoreceptor tyrosine-based inhibitory motif (ITIM)-like domain and the tyrosine phosphatase Corkscrew (Csw). Intriguingly, loss of Draper-II-Csw signaling prolongs expression of glial engulfment genes after axotomy and reduces the ability of glia to respond to secondary axotomy. Our work highlights a novel role for Draper-II in inhibiting glial responses to neurodegeneration, and indicates that a balance of opposing Draper-I and Draper-II signaling events is essential to maintain glial sensitivity to brain injury.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Axons / physiology*
  • Axotomy
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Immunoprecipitation
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Nerve Degeneration / metabolism*
  • Neuroglia / cytology
  • Neuroglia / physiology*
  • Neurons / cytology*
  • Olfactory Pathways / cytology
  • Olfactory Pathways / injuries
  • Phagocytosis / genetics
  • Phagocytosis / physiology
  • Protein Binding / genetics
  • Protein Interaction Domains and Motifs / genetics
  • Protein Interaction Domains and Motifs / physiology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism
  • RNA Interference / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Transcription Factors / metabolism

Substances

  • Drosophila Proteins
  • GAL4 protein, Drosophila
  • Membrane Proteins
  • Protein Isoforms
  • Transcription Factors
  • drpr protein, Drosophila
  • Green Fluorescent Proteins
  • Protein Tyrosine Phosphatases