title: WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling.
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.
authors.affiliation: Department of Molecular and Developmental Genetics, VIB, Center for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Thang Manh
authors.initials: TM
authors.lastname: Khuong
authors.forename: Ron L P
authors.initials: RL
authors.lastname: Habets
authors.forename: Jan R
authors.initials: JR
authors.lastname: Slabbaert
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D051316:Wiskott-Aldrich Syndrome Protein; C483010:nwk protein, Drosophila; C449821:wit protein, Drosophila; C071058:moesin