Neurexin and Frizzled signaling intercept axonal-transport at microtubule minus-ends to control synapse formation

Precise synaptic connectivity defines neuronal circuits. Synapse formation is locally determined by transmembrane proteins, yet synaptic material is synthesized remotely and undergoes processive transport in axons. How local synaptogenic signals intercept synaptic cargo in transport to promote its delivery and synapse formation is unknown. We found that control of synaptic cargo delivery at microtubule (MT) minus-ends mediates pro- and anti-synaptogenic activities of presynaptic Neurexin and Frizzled in C. elegans, and identified the atypical kinesin VAB-8/KIF26 as a key molecule in this process. VAB-8/KIF26 levels at synaptic MT minus-ends are controlled by Frizzled and Neurexin, its loss mimics neurexin mutants or Frizzled hyperactivation, and its overexpression can rescue synapse-loss in these backgrounds. VAB-8/KIF26 is required for the synaptic localization of other minus-end proteins and promotes pausing of retrograde transport to allow delivery to synapses. Consistently, reducing retrograde transport rescues synapse-loss in vab-8 and neurexin mutants. These results uncover an important mechanistic link between synaptogenic signaling and axonal transport.