The existence of distinct fast and slow components of axonal transport has been known for more than 25 years, but the mechanistic significance underlying these different rates of movement has been obscure for most of that time. The principal reason for this protracted period of uncertainty has been our inability to observe slow axonal transport directly in living cells. The recent discovery that cytoskeletal polymers conveyed by slow axonal transport actually move as fast as membranous organelles indicates that both fast and slow axonal transport may be generated by fast motors; cargoes as diverse as vesicles, mitochondria, and neurofilaments all move at comparable rates but they differ in the proportion of the time that they spend moving.
According to this unified perspective, membranous and nonmembranous cargoes are all transported along axons by the same underlying mechanism but they move at different rates due to differences in their duty ratio. Membranous organelles on the secretory and endocytic pathways, which function primarily to deliver membrane and protein components to sites along the axon and at the axon tip, move rapidly in a unidirectional manner, pausing for only brief periods of time. The high duty ratio of these organelles ensures that they are delivered rapidly to their destination. In contrast, cytoskeletal polymers, mitochondria, and possibly also endoplasmic reticulum, move in an intermittent and bidirectional manner, pausing more often and for longer periods of time, and sometimes reversing during their journey along the axon. Although we refer to these structures as cargoes, they are not simply the luggage of intracellular transport; these organelles and macromolecular assemblies are preassembled functional units that fulfill their architectural, physiological, and metabolic roles in the axon during their transit. For these cargoes, the journey is perhaps more important than the ultimate destination, and this may explain their unique motile behavior.
Based on these considerations, a central question underlying the difference between fast and slow axonal transport is the mechanism by which the movement of membranous and nonmembranous cargoes is regulated. For example, what determines whether a particular cytoskeletal polymer or membranous organelle moves or pauses, or how frequently it does so? And when movement does occur, what determines its direction and duration? Since the motile behavior of axonally transported cargoes determines the efficiency with which they are transported and the manner in which they are distributed along the axon, the regulation of this behavior is likely to be critical for many aspects of axonal structure and function. For example, in the case of mitochondria, the balance of anterograde and retrograde movements and pauses is regulated during axon growth in order to recruit these organelles to sites of metabolic demand (Morris and Hollenbeck, 1993
). Likewise, in the case of neurofilaments and microtubules, the balance of anterograde and retrograde movements and pauses is likely to be the principal determinant of their steady-state distribution along the axon, and thus the regulation of the axonal transport of these structures is probably essential for local and long-range remodeling of the neuronal cytoskeleton during axon growth and maturation. Since axonal transport continues throughout the life of the neuron, it is likely that active regulation of the movement of its membranous and nonmembranous components is an ongoing process as fundamental to the biology of axons as metabolism itself.