Abstract
The formation of synapses and the proper construction of neural circuits depend on signaling pathways that regulate cytoskeletal structure and dynamics. After the mutual recognition of a growing axon and its target, multiple signaling pathways are activated that regulate cytoskeletal dynamics to determine the morphology and strength of the connection. By analyzing Drosophila mutations in the cytoplasmic FMRP interacting protein Cyfip, we demonstrate that this component of the WAVE complex inhibits the assembly of filamentous actin (F-actin) and thereby regulates key aspects of synaptogenesis. Cyfip regulates the distribution of F-actin filaments in presynaptic neuromuscular junction (NMJ) terminals. At cyfip mutant NMJs, F-actin assembly was accelerated, resulting in shorter NMJs, more numerous satellite boutons, and reduced quantal content. Increased synaptic vesicle size and failure to maintain excitatory junctional potential amplitudes under high-frequency stimulation in cyfip mutants indicated an endocytic defect. cyfip mutants exhibited upregulated bone morphogenetic protein (BMP) signaling, a major growth-promoting pathway known to be attenuated by endocytosis at the Drosophila NMJ. We propose that Cyfip regulates synapse development and endocytosis by inhibiting actin assembly.
Highlights
To establish functional neural circuits, synapses must form at specific locations and grow to an appropriate size and strength
We propose that Cyfip regulates synaptic development and function by inhibiting filamentous actin (F-actin) assembly, which in turn downregulates bone morphogenetic protein (BMP) signaling via endocytosis
The total neuromuscular junction (NMJ) length was reduced by 50% in cyfip85.1 mutants relative to wild type (p,0.001; Figure 1A, 1B, and 1F), in agreement with a previous report [24]. cyfip hemizygous mutants in which cyfip85.1 was on one chromosome, while Df(3R)Exel6174, which uncovers cyfip, was on the other showed reduced NMJ length (p,0.001; Figure 1F)
Summary
To establish functional neural circuits, synapses must form at specific locations and grow to an appropriate size and strength. A multitude of signaling pathways are required to achieve and maintain these precise patterns of synaptic connectivity [1,2,3]. Many of these signals regulate local actin cytoskeletal networks, which are crucial for both synapse formation and plasticity [4,5,6]. Additional actin regulatory proteins implicated in synapse formation include WASP, spectrin, and adducin [6,9,10] These proteins and their interactors are conserved across species, indicating a seminal role for the actin cytoskeleton in synaptic development
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