Mitotic motors coregulate microtubule patterns in axons and dendrites.

Microtubules are nearly uniformly oriented in the axons of vertebrate neurons but are non-uniformly oriented in their dendrites. Studies to date suggest a scenario for establishing these microtubule patterns whereby microtubules are transported into the axon and nascent dendrites with plus-ends-leading, and then additional microtubules of the opposite orientation are transported into the developing dendrites. Here, we used contemporary tools to confirm that depletion of kinesin-6 (also called CHO1/MKLP1 or kif23) from rat sympathetic neurons causes a reduction in the appearance of minus-end-distal microtubules in developing dendrites, which in turn causes them to assume an axon-like morphology. Interestingly, we observed a similar phenomenon when we depleted kinesin-12 (also called kif15 or HKLP2). Both motors are best known for their participation in mitosis in other cell types, and both are enriched in the cell body and dendrites of neurons. Unlike kinesin-12, which is present throughout the neuron, kinesin-6 is barely detectable in the axon. Accordingly, depletion of kinesin-6, unlike depletion of kinesin-12, has no effect on axonal branching or navigation. Interestingly, depletion of either motor results in faster growing axons with greater numbers of mobile microtubules. Based on these observations, we posit a model whereby these two motors generate forces that attenuate the transport of microtubules with plus-ends-leading from the cell body into the axon. Some of these microtubules are not only prevented from moving into the axon but are driven with minus-ends-leading into developing dendrites. In this manner, these so-called "mitotic" motors coregulate the microtubule patterns of axons and dendrites.

A novel role for retrograde transport of microtubules in the axon.

Short microtubules move within the axon in both directions. In the past, it had been assumed that all of the short moving microtubules are oriented with their plus-ends distal to the cell body, regardless of their direction of movement. The anterogradely moving microtubules were posited to play critical roles in the establishment, expansion, and maintenance of the axonal microtubule array. There was no known function for the retrogradely moving microtubules. In considering the mechanism of their transport, we had assumed that all of the short microtubules have a plus-end-distal polarity orientation, as is characteristic of the long microtubules that dominate the axon. Here we discuss an alternative hypothesis, namely that the short microtubules moving retrogradely have the opposite polarity orientation of those moving anterogradely. Those that move anterogradely have their plus-ends distal to the cell body while those that move retrogradely have their minus ends distal to the cell body. In this view, retrograde transport is a means for clearing the axon of incorrectly oriented microtubules. This new model, if correct, has profound implications for the manner by which healthy axons preserve their characteristic pattern of microtubule polarity orientation. We speculate that pathological flaws in this mechanism may be a critical factor in the degeneration of axons during disease and injury, as well as in neuropathy caused by microtubule-active drugs.