Microtubule control of functional architecture in neurons

Abstract

Neurons are exquisitely polarized cells whose structure and function relies on microtubules. Microtubules in signal-receiving dendrites and signal-sending axons differ in their organization and microtubule-associated proteins. These differences, coupled with microtubule post-translational modifications, combine to locally regulate intracellular transport, morphology, and function. Recent discoveries provide new insight into the regulation of non-centrosomal microtubule arrays in neurons, the relationship between microtubule acetylation and mechanosensation, and the spatial patterning of microtubules that regulates motor activity and cargo delivery in axons and dendrites. Together, these new studies bring us closer to understanding how microtubule function is locally tuned to match the specialized tasks associated with signal reception and transmission.

Figure 1.. Microtubules carry out diverse roles within neurons.

Microtubules within axons and dendrites are distinctly organized. Axonal microtubules are uniformly oriented with their plus-ends positioned distal, or away from the cell body. Microtubules in the dendrites of invertebrate neurons are largely oriented with their plus-ends toward the cell body whereas microtubules in vertebrate dendrites typically have a mixed polarity. (B) αTAT1 acetylates α-tubulin at lysine 40, which is located within the microtubule lumen. Acetylated microtubules regulate mechanotransduction mediated by transmembrane channels, such as NOMPC, by tuning cell membrane stiffness and stabilizing microtubules. (C) Microtubules serve as the roads for plus-end-directed kinesin family members (top) and the minus-end-directed dynein motor complex (bottom). Transport into dendrites is controlled by microtubule organization, PTMs, and MAPs. In hippocampal neurons, microtubules of the same polarity are bundled together and marked by distinct post-translational modifications (tyrosination, acetylation). DCLK1 promotes the motility of kinesin-3 motors into dendrites along bundles of tyrosinated microtubules. Septin 9 selectively enhances kinesin-3 motility while preventing kinesin-1 from walking into dendrites. Instead, dendrite-localized kinesin-1 returns to the cell body along distinct tracks of acetylated microtubules. (D) BDNF stimulates microtubules to transiently grow into dendritic spines where they provide the tracks for the delivery of SytIV vesicles by kinesin-3 motors. BDNF likewise triggers the transport of TrkB vesicles by kinesin-4, a motor that also regulates microtubule plus-end dynamics. (E) MAP2 in the proximal axon blocks kinesin-1-mediated transport of DCVs and thus selects for DCVs carried by both kinesin-1 and kinesin-3, which coordinately transport DCVs to the axon terminal. The dynein cofactor Ndel1 is anchored in the proximal axon where it ‘catches’ dendritic cargoes, such as the transferrin receptor (TfR), and primes their transport by dynein into dendrites.