O'Connor-Giles Kate M, Ho Ling Ling, Ganetzky Barry
Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
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.
突触生长的调控对于神经回路的形成和可塑性至关重要。在此，我们证明了“神经破坏”（Nwk），果蝇神经肌肉接头处突触生长的负调控因子，在功能和物理上与内吞机制的组分相互作用，包括发动蛋白和Dap160/Intersectin，并通过与骨形态发生蛋白（BMP）受体“粗脉”的直接相互作用负调控逆行性BMP生长信号。Nwk中的突触过度生长对BMP信号水平敏感，且Nwk的缺失促进BMP诱导的过度生长。相反，Nwk的过表达抑制BMP诱导的突触过度生长。我们观察到dap160与BMP通路之间类似的遗传相互作用，证实内吞作用在神经肌肉接头处调节BMP信号。最后，我们证明了突触生长与磷酸化MAD（pMAD）水平之间的相关性，并表明Nwk调节这些水平。我们提出，Nwk在内吞作用和BMP信号的界面发挥作用，通过负调控“厚脉”（Tkv）来对这个正向生长信号设置限制，从而确保适当的突触生长。
