Figure 6.1 (a) Schematic of a neuron. Microtubules are oriented with their plus end projecting outward from the cell body. (b) Schematic of cytoskeletal organization within an axon. Microtubules populate the core of the axon, while actin is primarily localized to the periphery. Axons interact with their substrate through adhesion complexes. (c) Schematic of structural connectivity within an axon. Cytoskeletal elements may be cross-linked by rigid connectors or by dynamic motor proteins. Modified from Chetta et al. (2010). Reproduced with permission from Wiley-Liss, Inc.Axonal outgrowth is accompanied by a dramatic increase in cellular volume and surface area. In fact, single axons may be up to 1 m long in humans, with volumes up to, and in excess of, 1000 times that of the supporting cell body. This places a tremendous infrastructural and metabolic demand on the cell, both during development, to enable growth, and after maturity, to maintain homeostasis as well as respond to environmental cues. This demand is met in part through the bidirectional delivery of a variety of synaptic, metabolic, and structural proteins via molecular motor-mediated axonal transport upon a network of microtubule and actin filaments. The scope of the transport challenge is astounding; transported cargoes vary in size as well as function, ranging from vesicles to mitochondria to signaling complexes to entire segments of the cytoskeleton. Adding to this complexity,
axonal diameters may be as narrow as 200 nm, a dimension smaller than that of several transported cargoes themselves! Neurons must also overcome a biomechanical challenge. During outgrowth, and also in mature neurons, stability and instability in neuronal morphology is dictated by the delicate balance of forces resulting from interactions among the multiple force-generating and load-bearing components of the axon. Elements of the cytoskeleton as well as associated motor proteins, in addition to facilitating transport, are major contributors to such biomechanical roles. The careful organization of structural elements within the axon provides a unique and powerful model system in which interactions between structural elements may be investigated in the context of their transport as well as neuronal mechanics. Findings in neurons can subsequently be extended to elucidate general mechanisms guiding transport and biomechanics in cells with a more complex geometry. In this chapter, Section 6.2 will introduce the reader to the organization of major components of the structural framework and transport machinery within the neuron, Section 6.3 will expand upon axonal transport of the cytoskeleton, and Section 6.4 will summarize cytoskeletal contributions to neuronal cell mechanics. 6.2 Structural Organization within the NeuronStructural networks within the neuron may be represented as a dynamic array of filaments interconnected by various cross-link-ing elements. This network is coupled to a substrate through adhe-sive protein complexes (Fig. 6.1b,c). Filaments include members of the microtubule, microfilament (actin), and intermediate filament families. Cross-linking elements include both rigid connectors and dynamic motor proteins, the latter of which rely on the hydrolysis of ATP to fuel their movement along a specified track. Considerable biochemical, cellular biological, and biophysical evidence has elucidated details of how these components are organized within the neuron. General organization of actin, microtubules, and neurofilaments within the neuron is treated in this section. Implications for such organization for transport and mechanics are treated in greater detail in Sections 6.3 and 6.4.