Nervous Wreck Interacts With Thickveins and the Endocytic Machinery to Attenuate Retrograde BMP Signaling During Synaptic Growth

Neuron. 2008 May 22;58(4):507-18. doi: 10.1016/j.neuron.2008.03.007.


Regulation of synaptic growth is fundamental to the formation and plasticity of neural circuits. Here, we demonstrate that Nervous wreck (Nwk), a negative regulator of synaptic growth at Drosophila NMJs, interacts functionally and physically with components of the endocytic machinery, including dynamin and Dap160/intersectin, and negatively regulates retrograde BMP growth signaling through a direct interaction with the BMP receptor, thickveins. Synaptic overgrowth in nwk is sensitive to BMP signaling levels, and loss of Nwk facilitates BMP-induced overgrowth. Conversely, Nwk overexpression suppresses BMP-induced synaptic overgrowth. We observe analogous genetic interactions between dap160 and the BMP pathway, confirming that endocytosis regulates BMP signaling at NMJs. Finally, we demonstrate a correlation between synaptic growth and pMAD levels and show that Nwk regulates these levels. We propose that Nwk functions at the interface of endocytosis and BMP signaling to ensure proper synaptic growth by negatively regulating Tkv to set limits on this positive growth signal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Bone Morphogenetic Proteins / metabolism*
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Dynamins / metabolism
  • Endocytosis / physiology*
  • Larva
  • Membrane Proteins / metabolism
  • Mutation / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuromuscular Junction / physiology*
  • Presynaptic Terminals / physiology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction / physiology*
  • Two-Hybrid System Techniques
  • Vesicular Transport Proteins / metabolism


  • Bone Morphogenetic Proteins
  • Dap160 protein, Drosophila
  • Drosophila Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Vesicular Transport Proteins
  • nwk protein, Drosophila
  • tkv protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • Dynamins