Self-organization of the microtubule cytoskeleton in developing axons

Disruption of axonal microtubule arrays is a key factor in nerve degeneration associated with neurodegenerative diseases such as Alzheimer's. In developing axons, nearly all MTs are oriented with their plus ends away from the cell body, referred to as a “plus-end-out” polarity pattern. This uniform polarity pattern is under continual threat of corruption in the face of nucleation of new MTs and “flipping” of short MTs into a minus-end-out orientation. Here, we present a computational study using agent-based simulations and visual animations to demonstrate how the self-organizing properties of the cytoskeleton contribute to the establishment and maintenance of the MT polarity pattern in axons. We show that occasional minus-end-out MTs can be cleared from the axon through a “polarity sorting” mechanism in which cytoplasmic dynein slides anti-parallel MTs with their plus-ends leading. We identify conditions under which a simple dynein-based polarity-sorting mechanism is insufficient to prevent MT polarity flaws from accumulating. Our simulations exhibit a positive feedback loop that emerges when mis-oriented MTs grow and incorporate into the MT array, and in turn undermine the efficiency of motor-based polarity-sorting in clearing new minus-end-out MTs from the axon. We hypothesize that a static crosslinking protein, such as TRIM46, which resists relative sliding between parallel MTs plays an essential role in “error prevention” by stabilizing the plus-end-out MT array while allowing dynein-based polarity sorting to remove occasional minus-end-out MTs. We further hypothesize that another static crosslinker, such as PRC1, may boost the efficiency of polarity sorting by aligning anti-parallel MTs to facilitate dynein-based sliding. Initial experiments demonstrate that inhibition of these candidate crosslinking proteins produces an increase in MT polarity flaws in vertebrate axons, in support of our model for a multiple-player polarity-sorting mechanism in the axonal MT array.