WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling.
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.
Khuong
Thang Manh
TM
Department of Molecular and Developmental Genetics, VIB, Center for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Habets
Ron L P
RL
Slabbaert
Jan R
JR
Verstreken
Patrik
P
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*
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