Microtubule‐binding protein doublecortin‐like kinase 1 (DCLK1) guides kinesin‐3‐mediated cargo transport to dendrites

Abstract

In neurons, the polarized distribution of vesicles and other cellular materials is established through molecular motors that steer selective transport between axons and dendrites. It is currently unclear whether interactions between kinesin motors and microtubulebinding proteins can steer polarized transport. By screening all 45 kinesin family members, we systematically addressed which kinesin motors can translocate cargo in living cells and drive polarized transport in hippocampal neurons. While the majority of kinesin motors transport cargo selectively into axons, we identified five members of the kinesin-3 (KIF1) and kinesin-4 (KIF21) subfamily that can also target dendrites. We found that microtubulebinding protein doublecortin-like kinase 1 (DCLK1) labels a subset of dendritic microtubules and is required for KIF1-dependent dense-core vesicles (DCVs) trafficking into dendrites and dendrite development. Our study demonstrates that microtubule-binding proteins can provide local signals for specific kinesin motors to drive polarized cargo transport.

Mechanisms and functions of lysosome positioning

“…Other MAPs (e.g. ensconsin and DCLK1), however, promote recruitment and activation of kinesins on specific populations of microtubules (Sung et al, 2008;Lipka et al, 2016). Finally, KBPs can modulate kinesin activity, as shown for the inactivation of the motor domains of the kinesin-3 KIF1A and kinesin-8 KIF18A by the protein KBP (also known as KIF1BP and KIAA1279) (Kevenaar et al, 2016).…”

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

“…4-6). In fact, many of the ∼45 mammalian kinesins exclusively mediate axonal transport, and only a handful, including the kinesin-3 proteins KIF1A, KIF1Bβ, KIF1C, and KIF16B and the kinesin-4 proteins KIF21A and KIF21B, mediate organelle transport to axons and dendrites (24,25,67). Of these, KIF1A and KIF1Bβ have been reported to move late endosomes and lysosomes in nonneuronal cells (54,68,69).…”

“…These distinct properties determine the specificity and direction of organelle movement by different microtubule motors in different regions of the neuron. Of the ∼45 kinesins encoded in mammalian genomes, many mediate axonal anterograde transport, whereas a few additionally drive transport in the dendrites (23)(24)(25). In contrast, there is only one cytoplasmic dynein in mammals that mediates retrograde transport in the axon, as well as transport in the dendrites (26,27).…”

Intracellular cargo transport by kinesin-3 motors

“…DCLK 1 specifically binds to microtubules in dendrites, which acts as a positive signal to promote dendritic transport of KIF1 cargoes. In the absence of DCLK 1, KIF1 motors predominantly trans port DCVs into the axon [117]. In C. elegans, the retro grade motility of Unc 104 was affected in tau/PTL 1 (protein with tau like repeats) knockout worms.…”