A JNK-interacting protein 1 acts across the midline to mediate synaptic localization of the SARM1 calcium-signaling scaffold protein for asymmetric neuronal fate choice

The Caenorhabditis elegans AWC olfactory neuron pair specifies asymmetric subtypes, AWC ^OFF and AWC ^ON , through stochastic and coordinated cell signaling events. UNC-104/kinesin-3 (KIF1A) and UNC-116/kinesin-1 motor proteins act in the AWC ^ON cell to regulate the synaptic localization of the TIR-1/SARM1-assembled calcium signaling complex in the AWC ^OFF cell to promote AWC ^OFF . However, the molecular mechanism in the AWC ^ON cell that acts non-cell autonomously to control synaptic TIR-1 calcium signaling to promote AWC ^OFF remains unclear. Here, we show that JIP-1, a conserved c-Jun N-terminal kinase (JNK)-interacting protein 1, mediates the synaptic localization of TIR-1 in the AWC axon to specify the AWC ^OFF subtype. A jip-1 loss-of-function mutant, identified from an unbiased forward genetic screen, has reduced localization of TIR-1 at synapses in the AWC axon and accumulation of TIR-1 in the AWC cell body. jip-1 mutants significantly enhance the 2AWC ^ON phenotype of a hypomorphic tir-1 mutant. JIP-1, like UNC-104 and UNC-116, mainly acts non-cell autonomously in AWC ^ON to specify the AWC ^OFF subtype. Our findings provide mechanistic insights into how cell-specific Ca ²⁺ signaling proteins, such as TIR-1, target synaptic regions via intercellular signaling to promote neuronal diversification.