Differentiation between Oppositely Oriented Microtubules Controls Polarized Neuronal Transport

Abstract

SummaryMicrotubules are essential for polarized transport in neurons, but how their organization guides motor proteins to axons or dendrites is unclear. Because different motors recognize distinct microtubule properties, we used optical nanoscopy to examine the relationship between microtubule orientations, stability, and modifications. Nanometric tracking of motors to super-resolve microtubules and determine their polarity revealed that in dendrites, stable and acetylated microtubules are mostly oriented minus-end out, while dynamic and tyrosinated microtubules are oriented oppositely. In addition, microtubules with similar orientations and modifications form bundles that bias transport. Importantly, because the plus-end-directed Kinesin-1 selectively interacts with acetylated microtubules, this organization guides this motor out of dendrites and into axons. In contrast, Kinesin-3 prefers tyrosinated microtubules and can enter both axons and dendrites. This separation of distinct microtubule subsets into oppositely oriented bundles constitutes a key architectural principle of the neuronal microtubule cytoskeleton that enables polarized sorting by different motor proteins.

A novel strategy to visualize vesicle‐bound kinesins reveals the diversity of kinesin‐mediated transport

“…In dendrites, no kinesins labeled vesicles with a strong directionality preference (Figure B). This is consistent with the mixed orientation of dendritic microtubules, which could enable kinesins to mediate both anterograde and retrograde transport …”

Polarity of Neuronal Membrane Traffic Requires Sorting of Kinesin Motor Cargo during Entry into Dendrites by a Microtubule-Associated Septin

“…A parsimonious explanation is that SEPT9 marks and/or bridges MTs of plus-end-out orientation. While this article was under review, it was reported that kinesin-1/KIF5 associates preferentially with acetylated MTs of minus-end-out orientation and kinesin-3/KIF1A interacts with dynamic tyrosinated MTs, which are oriented with their plus ends out (Tas et al, 2017). Hence, SEPT9 may have a role in the regulation of membrane traffic on the plus-end-out subsets of MTs.…”

Kinesin-2 heterodimerization alters entry into a processive run along the microtubule but not stepping within the run

“…In contrast, KIF3AB is ubiquitously expressed including neurons (2-4, 34), but our best understanding of KIF3AB transport is for intraflagellar transport in cilia. One testable hypothesis for future investigation is whether KIF3AC and KIF3AB in neurons read the tubulin code differently based on posttranslational modifications of the axonal versus dendritic microtubules to bias selective transport of cargos to enter axons or dendrites (34,(53)(54)(55).…”

“…In contrast, KIF3AB is ubiquitously expressed including neurons (2-4, 34), but our best understanding of KIF3AB transport is for intraflagellar transport in cilia. One testable hypothesis for future investigation is whether KIF3AC and KIF3AB in neurons read the tubulin code differently based on posttranslational by guest on April 27, 2019 http://www.jbc.org/ Downloaded from 9 modifications of the axonal versus dendritic microtubules to bias selective transport of cargos to enter axons or dendrites (34,(53)(54)(55).In summary, mathematical modeling has provided new insights to understand the motile properties of KIF3AC and KIF3AB. These results revealed that microtubule association for KIF3AC and KIF3AB is an emergent property due to heterodimerization, and once in the processive run, the rates of the nucleotide-dependent transitions result from the relative intrinsic catalytic properties of the motor domains.…”