WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling

Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17379-84. doi: 10.1073/pnas.1001794107. Epub 2010 Sep 15.

Abstract

Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)] is a membrane lipid involved in several signaling pathways. However, the role of this lipid in the regulation of synapse growth is ill-defined. Here we identify PI(4,5)P(2) as a gatekeeper of neuromuscular junction (NMJ) size. We show that PI(4,5)P(2) levels in neurons are critical in restricting synaptic growth by localizing and activating presynaptic Wiscott-Aldrich syndrome protein/WASP (WSP). This function of WSP is independent of bone morphogenetic protein (BMP) signaling but is dependent on Tweek, a neuronally expressed protein. Loss of PI(4,5)P(2)-mediated WSP activation results in increased formation of membrane-organizing extension spike protein (Moesin)-GFP patches that concentrate at sites of bouton growth. Based on pharmacological and genetic studies, Moesin patches mark polymerized actin accumulations and correlate well with NMJ size. We propose a model in which PI(4,5)P(2)- and WSP-mediated signaling at presynaptic termini controls actin-dependent synapse growth in a pathway at least in part in parallel to synaptic BMP signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / anatomy & histology
  • Drosophila melanogaster / physiology
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuromuscular Junction / physiology
  • Neuromuscular Junction / ultrastructure
  • Patch-Clamp Techniques
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / ultrastructure
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology*
  • Synapses / physiology*
  • Synapses / ultrastructure
  • Wiskott-Aldrich Syndrome Protein / genetics
  • Wiskott-Aldrich Syndrome Protein / metabolism*

Substances

  • Bone Morphogenetic Proteins
  • Drosophila Proteins
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • Wiskott-Aldrich Syndrome Protein
  • nwk protein, Drosophila
  • wit protein, Drosophila
  • moesin