Abstract
The authors provide genetic and cell-biological evidence indicating that MIG-10B interacts with ABI-1 to organize the actin cytoskeleton at presynaptic sites and that the
C. elegans
Synapsin ortholog snn-1 acts downstream from MIG-10B to instruct synaptic vesicle clustering at presynaptic sites, likely bridging vesicle interaction with the MIG-10B-organized actin cytoskeleton. The findings support a model in which MIG-10B localizes to presynaptic sites in response to Netrin, organizes the actin cytoskeleton through an ABI-1-mediated interaction with the WAVE complex, and instructs vesicle clustering at presynaptic sites through Synapsin.
The chemotrophic factor Netrin can simultaneously instruct different neurodevelopmental programs in individual neurons in vivo. How neurons correctly interpret the Netrin signal and undergo the appropriate neurodevelopmental response is not understood. Here we identify MIG-10 isoforms as critical determinants of individual cellular responses to Netrin. We determined that distinct MIG-10 isoforms, varying only in their N-terminal motifs, can localize to specific subcellular domains and are differentially required for discrete neurodevelopmental processes in vivo. We identified MIG-10B as an isoform uniquely capable of localizing to presynaptic regions and instructing synaptic vesicle clustering in response to Netrin. MIG-10B interacts with Abl-interacting protein-1 (ABI-1)/Abi1, a component of the WAVE complex, to organize the actin cytoskeleton at presynaptic sites and instruct vesicle clustering through SNN-1/Synapsin. We identified a motif in the MIG-10B N-terminal domain that is required for its function and localization to presynaptic sites. With this motif, we engineered a dominant-negative MIG-10B construct that disrupts vesicle clustering and animal thermotaxis behavior when expressed in a single neuron in vivo. Our findings indicate that the unique N-terminal domains confer distinct MIG-10 isoforms with unique capabilities to localize to distinct subcellular compartments, organize the actin cytoskeleton at these sites, and instruct distinct Netrin-dependent neurodevelopmental programs.
