Highwire Regulates Presynaptic BMP Signaling Essential for Synaptic Growth

Neuron. 2004 Mar 25;41(6):891-905. doi: 10.1016/s0896-6273(04)00073-x.

Abstract

Highwire (Hiw), a putative RING finger E3 ubiquitin ligase, negatively regulates synaptic growth at the neuromuscular junction (NMJ) in Drosophila. hiw mutants have dramatically larger synaptic size and increased numbers of synaptic boutons. Here we show that Hiw binds to the Smad protein Medea (Med). Med is part of a presynaptic bone morphogenetic protein (BMP) signaling cascade consisting of three receptor subunits, Wit, Tkv, and Sax, in addition to the Smad transcription factor Mad. When compared to wild-type, mutants of BMP signaling components have smaller NMJ size, reduced neurotransmitter release, and aberrant synaptic ultrastructure. BMP signaling mutants suppress the excessive synaptic growth in hiw mutants. Activation of BMP signaling, which in wild-type does not cause additional growth, in hiw mutants does lead to further synaptic expansion. These results reveal a balance between positive BMP signaling and negative regulation by Highwire, governing the growth of neuromuscular synapses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Differentiation / genetics*
  • Cell Size / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / growth & development*
  • Drosophila melanogaster / metabolism
  • Drosophila melanogaster / ultrastructure
  • Microscopy, Electron
  • Motor Neurons / cytology
  • Motor Neurons / metabolism
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuromuscular Junction / growth & development*
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / ultrastructure
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / pathology
  • Presynaptic Terminals / ultrastructure
  • Protein Binding / genetics
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / genetics
  • Smad4 Protein
  • Synaptic Transmission / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • HIW protein, Drosophila
  • Med protein, Drosophila
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Receptors, Transforming Growth Factor beta
  • Smad4 Protein
  • Trans-Activators
  • sax protein, Drosophila
  • wit protein, Drosophila