Highwire Regulates Presynaptic BMP Signaling Essential for Synaptic Growth

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...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2004-03, Vol.41 (6), p.891-905
Main Authors: McCabe, Brian D, Hom, Sabrina, Aberle, Hermann, Fetter, Richard D, Marques, Guillermo, Haerry, Theodore E, Wan, Hong, O'Connor, Michael B, Goodman, Corey S, Haghighi, A.Pejmun
Format: Article
Language:English
Subjects:
Animals
Bone Morphogenetic Proteins - genetics
Bone Morphogenetic Proteins - metabolism
Cell Differentiation - genetics
Cell Size - genetics
Defects
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Drosophila melanogaster
Drosophila melanogaster - growth & development
Drosophila melanogaster - metabolism
Drosophila melanogaster - ultrastructure
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Enzymes
Highwire protein
Hiw gene
Insects
Kinases
Ligands
Microscopy
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
Proteins
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Receptors, Transforming Growth Factor beta - genetics
Receptors, Transforming Growth Factor beta - metabolism
Sax protein
Signal Transduction - genetics
Smad4 Protein
Synaptic Transmission - genetics
Tkv protein
Trans-Activators - genetics
Trans-Activators - metabolism
Wit protein
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Summary: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.
ISSN:0896-6273
1097-4199
DOI:10.1016/S0896-6273(04)00073-X