Introduction

Neurons are highly polarized cells, typically consisting of a cell body, several dendrites, and a long, thin axon. The soma or perikaryon contains the nucleus, endoplasmic reticulum, mitochondria, the Golgi apparatus, and a large number of cytoskeletal fibers. The axon and the dendrites are processes, which arise from the cell body and differ in terms of shape, cytoskeletal organization, and membrane protein composition. The region of the cell body from which axons originate is known as the axon hillock, a narrow structure that tapers off to the axon initial segment. In contrast to axons, dendrites have a larger diameter and taper off gradually. Proximal dendrites are abundant in endoplasmic reticulum and ribosomes and the cytoskeletal architecture of proximal dendrites and the cell body is similar. Distal dendrites also contain endoplasmic reticulum and ribosomes and are thought to synthesize individual proteins. For local protein synthesis of individual proteins, specific mRNAs are also transported to distal dendrites. A key problem in intracellular transport is the fact that neurites extend distances that are hundreds or thousands of times the diameter of the cell body (Figure 13.1). Therefore, efficient transport mechanisms are required to recruit mRNAs and a large number of newly synthesized proteins to neurites.

Long-distance transport is mainly mediated by microtubules, cytoskeletal fibers that serve as tracks for the transport of molecules. Microtubules are long hollow cylinders and their polarity differs between axons and dendritic compartments. Significantly, neurons have multiple compartments that are devoid of microtubules where transport is still seen to occur. These areas are rich in other cytoskeletal polymers such as actin filaments, which are typically used as tracks for short-distance transport. Actin filaments also display a polarity in the polymer with a pointed- and a barbed-end and are highly enriched at the cellular cortex1.

3. ORGANIZATION AND POLARITY OF MICROTUBULES, THE TRACKS FOR LONG-DISTANCE TRANSPORT

Microtubules are polymers of a and P tubulins with a fast-growing (plus) end and an opposite slow-growing (minus) end2. Microtubules associate with microtubule-associated proteins (MAPs) and are highly crosslinked by meshworks of fine filamentous structures. The spacing of microtubules in axons is about 20 nm, whereas in dendrites it is typically 65 nm. Some MAPs selectively localize either to the axon or the dendrite. Whereas the MAP tau decorates microtubules in the axon, MAP2 binds to microtubules in dendrites.

Microtubules generally have a radial organization in many cell types, with plus ends typically oriented to the cell periphery and minus ends anchored in a microtubule-organizing center (MTOC). With respect to neurons, this uniformity of microtubule polarity is found in axons but not in dendrites. Axonal microtubules are directed with their plus ends away from the cell body toward the growth cone. In contrast, dendritic microtubules show a mixed orientation. In proximal dendritic regions, about 75 p.m from the cell body, roughly equal proportions of micro-tubules are oriented with plus ends directed either toward the growth cone or toward the cell body. However, in distal dendritic regions, within about 15-p.m distances from the growth cone, microtubule polarity orientation is similar to that in axons, thus plus ends are uniformly directed toward the growth cone. Molecular motors of the kinesin and dynein superfamilies move along microtubules. Most kinesin superfamily proteins (KIFs) represent plus-end directed motors that move toward the plus end of microtubules3. This direction from the cell body to axons and dendrites is considered as anterograde transport. Dyneins are minus-end directed microtubule motors that mediate retrograde transport from the axonal and dendritic terminals to the cell body4. In contrast, myosin motors use actin filaments as tracks for transport and most myosins move toward the barbed or plus end of the filament.

Figure 13.1. The Transport Problem. Schematic representation of the relationship between axon length and size of the perikaryon in a human motoneuron. Proteins that are synthesized in the neuronal perikaryon (black circle) need to travel distances that are a few orders of magnitude the diameter of the cell body. The preferential delivery to a specific subcellular compartment such as an axon, the transport over long distances, and the constant delivery of material to neurite processes or synapses is a great challenge for the cellular transport machinery.

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