Principles of microtubule polarity in linear cells

Abstract

The microtubule cytoskeleton is critical for maintenance of long and long-lived neurons. The overlapping array of microtubules extends from the major site of synthesis in the cell body to the far reaches of axons and dendrites. New materials are transported from the cell body along these neuronal roads by motor proteins, and building blocks and information about the state of affairs in other parts of the cell are returned by motors moving in the opposite direction. As motor proteins walk only in one direction along microtubules, the combination of correct motor and correctly oriented microtubules is essential for moving cargoes in the right direction. In this review, we focus on how microtubule polarity is established and maintained in neurons. At first thought, it seems that figuring out how microtubules are organized in neurons should be simple. After all, microtubules are essentially sticks with a slow-growing minus end and faster-growing plus end, and arranging sticks within the constrained narrow tubes of axons and dendrites should be straightforward. It is therefore quite surprising how many mechanisms contribute to making sure they are arranged in the correct polarity. Some of these mechanisms operate to generate plus-end-out polarity of axons, and others control mixed or minus-end-out dendrites.

Keywords: Kinesin; Microtubule; Neuron; Polarity.

Figure 1.

Axonal polarity control mechanisms In all diagrams the cell body is at the left and axon is shown extending to the right. The microtubule of interest is shown in blue with plus end indicated. Older or template microtubules are shown in grey. A. Dynamic plus ends can grow out from the cell body into the axon during development and in mature neurons. Rapid plus end growth can help populate axons with plus-end-out microtubules. B. Dynein anchored to the cell cortex can slide mis-oriented microtubules out of the axon by walking towards their minus end. Plus end growth and dynein-mediated removal of microtubules can help establish initial polarity, and can also help maintain polarity over the long-term. C. The HAUS/augmin complex can recruit the gamm-tubulin ring complex to the side of existing microtubules and favors nucleation in parallel to the template. D. A microtubule severing event can generate two new correctly oriented microtubules from a parent microtubule. Minus ends are typically recognized by capping proteins including CAMSAPs when they are generated. Both severing and templated nucleation help maintain microtubule polarity by making new microtubules based on the polarity of pre-existing microtubules.

Figure 2.

Dendritic microtubule polarity control mechanisms In all diagrams the dendrite is at the left and cell body at right. Microtubules are drawn as in Figure 1. Endosomal nucleation sites are shown as magenta circles. A. Minus end outgrowth from the cell body into dendrites is slow and persistent, and can contribute to presence of minus-end-out microtubules in dendrites. B. In developing C. elegans neurons positioning of nucleation sites near the growing tip helps establish minus-end-out polarity (not shown). In Drosophila nucleation at dendrite branch points is biased towards the cell body. It is not clear whether this bias depends on the polarity of pre-existing microtubules or whether it is independent of them and could thus help establish minus-end-out polarity. C. New microtubules nucleated at dendrite branch points in Drosophila are more likely to succeed in growing beyond the branch point if they are oriented in the same direction as existing microtubules. Thus in a minus-end-out dendrite arbor, new microtubule growth towards the cell body is favored maintaining existing polarity. D. Kinesin-2 can be recruited to growing plus ends of microtubules and can steer the plus end along the side of a pre-existing microtubule it collides with thus reinforcing existing polarity.