Polarity of Neuronal Membrane Traffic Requires Sorting of Kinesin Motorcargo During Entry into Dendrites by a Microtubule-Associated Septin

Neuronal function requires axon-dendrite membrane polarity, which depends on sorting of membrane traffic during entry into axons. Due to a microtubule network of mixed polarity, dendrites receive vesicles from the cell body without apparent capacity for directional sorting. We found that in the initial segments of dendrites, axonally-destined cargos move with a retrograde bias toward the cell body, while dendritically-destined cargos are biased in the anterograde direction. A microtubule-associated septin (SEPT9), which localizes specifically in dendrites, impedes axonal cargo of kinesin-1/KIF5 and boosts kinesin-3/KIF1 motor-cargo further into dendrites. In neurons and in vitro single-molecule motility assays, SEPT9 suppresses kinesin-1/KIF5 and enhances kinesin-3/KIF1 in a manner that depends on a lysinerich loop of the kinesin motor domain. This differential regulation impacts partitioning of neuronal membrane proteins into axonsdendrites. Thus, polarized membrane traffic requires sorting during entry into dendrites by a septin-mediated mechanism that bestows directional bias on microtubules of mixed orientation.