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.