Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1

Nat Commun. 2015 Sep 24;6:8302. doi: 10.1038/ncomms9302.

Abstract

The functional assembly of the synaptic release machinery is well understood; however, how signalling factors modulate this process remains unknown. Recent studies suggest that Wnts play a role in presynaptic function. To examine the mechanisms involved, we investigated the interaction of release machinery proteins with Dishevelled-1 (Dvl1), a scaffold protein that determines the cellular locale of Wnt action. Here we show that Dvl1 directly interacts with Synaptotagmin-1 (Syt-1) and indirectly with the SNARE proteins SNAP25 and Syntaxin (Stx-1). Importantly, the interaction of Dvl1 with Syt-1, which is regulated by Wnts, modulates neurotransmitter release. Moreover, presynaptic terminals from Wnt signalling-deficient mice exhibit reduced release probability and are unable to sustain high-frequency release. Consistently, the readily releasable pool size and formation of SNARE complexes are reduced. Our studies demonstrate that Wnt signalling tunes neurotransmitter release and identify Syt-1 as a target for modulation by secreted signalling proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Dishevelled Proteins
  • Fluorescent Antibody Technique
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Neurons / metabolism*
  • Neurotransmitter Agents / metabolism*
  • Patch-Clamp Techniques
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission
  • Synaptic Vesicles / metabolism*
  • Synaptosomal-Associated Protein 25 / metabolism*
  • Synaptotagmin I / metabolism*
  • Syntaxin 1 / metabolism*
  • Wnt Proteins / genetics
  • Wnt Signaling Pathway*

Substances

  • Adaptor Proteins, Signal Transducing
  • Dishevelled Proteins
  • Dvl1 protein, mouse
  • Dvl1 protein, rat
  • Neurotransmitter Agents
  • Phosphoproteins
  • Synaptosomal-Associated Protein 25
  • Synaptotagmin I
  • Syntaxin 1
  • Wnt Proteins
  • Wnt7a protein, mouse