Kinesin-1 trans-synaptically regulates synaptic localization of SARM1 for asymmetric neuron diversification

The <i>Caenorhabditis elegans</i> AWC olfactory neuron pair differentiates stochastically into two distinct subtypes, default AWC^OFF and induced AWC^ON. A calcium signaling complex assembled by the TIR-1/SARM1 adaptor protein is transported from the AWC cell body to the axons, where it cell autonomously specifies the AWC^OFF subtype through lateral signaling. UNC-104, the <i>C. elegans</i> homolog of the kinesin-3 motor protein KIF1A, acts non-cell autonomously in AWC^ON to control the synaptic localization of the TIR-1 signaling complex in promoting AWC^OFF. Here, we identify a non-cell-autonomous role of <i>unc-116/kinesin-1</i>, similar to that of <i>unc-104/kinesin-3</i>, in promoting AWC^OFF. <i>unc-116</i> mutants, similar to <i>unc-104</i> mutants, enhance the 2AWC^ON phenotype of a hypomorphic <i>tir-1</i> mutant. Overexpression of <i>unc-116</i> in AWC causes a 2AWC^OFF phenotype, the same as the <i>tir-1</i> overexpression phenotype. Like UNC-104, UNC-116 plays a non-cell-autonomous role in the AWC^ON cell to promote AWC^OFF cell subtype by regulating the dynamic trafficking of TIR-1 along the AWC axon. UNC-116 is strikingly colocalized with UNC-104, while both are generally adjacent to TIR-1. Taken together, these results suggest a model in which UNC-116/kinesin-1 and UNC-104/kinesin-3 may work cooperatively to transport some unknown presynaptic factor(s) in the future AWC^ON cell that trans-synaptically regulates the dynamic trafficking of the TIR-1/SARM1 signaling complex to postsynaptic regions of the AWC axons in promoting the AWC^OFF subtype.