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NAB-1 instructs synapse assembly by linking adhesion molecules and F-actin to active zone proteins

Abstract

During synaptogenesis, macromolecular protein complexes assemble at the pre- and postsynaptic membrane. Extensive literature identifies many transmembrane molecules sufficient to induce synapse formation and several intracellular scaffolding molecules responsible for assembling active zones and recruiting synaptic vesicles. However, little is known about the molecular mechanisms coupling membrane receptors to active zone molecules during development. Using Caenorhabditis elegans, we identify an F-actin network present at nascent presynaptic terminals and required for presynaptic assembly. We unravel a sequence of events whereby specificity-determining adhesion molecules define the location of developing synapses and locally assemble F-actin. Next, the adaptor protein NAB-1 (neurabin) binds to F-actin and recruits active zone proteins SYD-1 and SYD-2 (liprin-α) by forming a tripartite complex. NAB-1 localizes transiently to synapses during development and is required for presynaptic assembly. Altogether, we identify a role for the actin cytoskeleton during presynaptic development and characterize a molecular pathway whereby NAB-1 links synaptic partner recognition to active zone assembly.

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Figure 1: F-actin localizes to HSN synapses and is required for presynapse assembly.
Figure 2: NAB-1 localizes to presynaptic sites and nab-1 mutants show presynaptic assembly defects.
Figure 3: NAB-1 is an actin-binding protein that localizes to presynapses by binding to F-actin.
Figure 4: NAB-1 requires SYG-1 for synaptic localization and functions downstream of F-actin.
Figure 5: NAB-1 functions in the L4 stage early during synaptogenesis.
Figure 6: NAB-1 functions upstream and is required to recruit both active zone scaffolding molecules SYD-1 and SYD-2.
Figure 7: NAB-1 recruits downstream active zone molecules by interacting with SYD-1 and SYD-2.

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Acknowledgements

We thank the Caenorhabditis Genetics Center and Japanese National Bioresource Project for strains. We also thank C. Gao and Y. Fu for technical assistance and T. Clandinin, K. Zito, K. Mizumoto, C.Y. Ou and Shen laboratory members for manuscript comments. This work was funded by the Howard Hughes Medical Institute and US National Institutes of Health grant R01 NS048392. P.H.C. is supported by the Agency for Science, Technology, and Research (Singapore).

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P.H.C. and K.S. designed experiments and wrote the paper. M.R.P. made initial observations and performed initial experiments. P.H.C. performed experiments and analyzed the data.

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Correspondence to Kang Shen.

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Chia, P., Patel, M. & Shen, K. NAB-1 instructs synapse assembly by linking adhesion molecules and F-actin to active zone proteins. Nat Neurosci 15, 234–242 (2012). https://doi.org/10.1038/nn.2991

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