The Axon

PNS and CNS axons have a similar structure. Indeed, many axons (motor axons, preganglionic autonomic axons, primary sensory axons) course uninterrupted from the CNS to the PNS or vice versa. The axon membrane (the axolemma), which is about 8 nm thick, contains key molecules responsible for maintaining the resting potential and for action potential generation and propagation (voltage gated ionic channels, ion pumps, enzymes, cell adhesion molecules). Examination of the axolemma by freeze fracture electron microscopy (EM) shows that the outside of the inner leaflet (the P-face) displays numerous particles assumed to represent macromolecules. In unmyelinated axons, the inside of the outer leaflet (the E-face) presents few particles. However, at initial axon segments and at nodes of Ranvier in myelinated axons, the E-face exhibits clusters of 10 nm particles, which may be related to sodium channels (Fig. 13; Rosenbluth, 1976, see further later). Subjacent to the axolemma there is a cytoskeletal cortex (Ichimura and Ellisman, 1991).

The axolemma encloses cytosol, axoplasmic organelles and inclusions. Axonal mitochondria are prominent among the organelles (Fig. 2). A typical axonal mitochondrion is 0.1 to 0.3 |im thick and 0.5 to more than 10 |im long, and the cristae are longitudinally oriented. In transverse sections the mitochondrial concentration varies from 2/| m2 axoplasm in unmyelinated axons to 0.1/|m2 axoplasm in myelinated axons. The axoplasmic reticulum, a system of membranous tubules (20 to 60 nm) and flattened sacs (<100 nm), extends from the axon hillock to the axon terminals (Fig. 2). It may be involved in slow anterograde transport and it acts as a reservoir for calcium ions (see Berthold and Rydmark, 1995).

Figure 2 Electron micrograph showing axoplasm of a transversely sectioned large mammalian myelinated axon (nf = neurofilaments; nt = neuro-tubules; mt = mitochondria; e = axoplasmic reticulum). Scale bar = 0.5 |m. (With permission from Landon, 1981.)

The cytoskeleton includes microtubules, neurofilaments, and the microtrabecular matrix (Figs. 2 and 3). Axonal microtubules resemble microtubules elsewhere, that is, 25-nm, thick, unbranched discontinuous tubes. Thin axons have 100 microtubules/|m2 cross-sectional area, and thick axons 10/|m2. The average microtubule length seems to be relatively limited (Tsukita and Ishikawa, 1981: 370-760 |im; Bray and Bunge, 1981: 108 |im). They have a light core surrounded by a 6-nm thick wall composed of 13 protofilaments (Figs. 2 and 3). The filaments consist of tubulin subunits, each of which is a heterodimer of two globular proteins (a-tubulin and P-tubulin) bound together. The end of a microtubule pointing away from the cell body (the plus end, P subunits exposed) is where new monomers are added for growth. The other end (the minus end, a subunits exposed) is where monomers are removed for shortening. A major function of microtubules is to provide tracks for fast anterograde transport, mediated by kinesin, and fast retrograde transport mediated by dynein (see Berthold and Rydmark, 1995; Alberts et al., 2002).

Neurofilaments, 10-nm unbranched stable fibers of unknown length, belong to the family of intermediate filaments (Figs. 2 and 3). There are 150 to 300 neurofilaments/^2 axoplasm, independent of axon size (Hirano and Dembitzer, 1978). Three types of neurofilament protein (NFL, 68 kD; NF-M, 150 kD; NF-H, 200 kD) coassemble in vivo to heteropolymers with NF-L plus one of the others. The neurofilaments are linked together by protein cross-bridges believed to contribute to the tensile strength of the axon and accounting for the regular interfilament spacing (Fig. 3)

Figure 3 Electron micrograph showing part of an axon in a quick-frozen and deep-etched frog spinal nerve treated with saponin. Microtubules (m) and neurofilaments (nf) are shown. The microtubules, which were stabilized with taxol, run across the central part of the field in a bundle. The protofilaments are clearly visible. Some cross-bridges join adjacent microtubules. The neurofilaments are also linked by cross-bridges (x200,000). (With permission from Peters et al., 1991.)

Figure 3 Electron micrograph showing part of an axon in a quick-frozen and deep-etched frog spinal nerve treated with saponin. Microtubules (m) and neurofilaments (nf) are shown. The microtubules, which were stabilized with taxol, run across the central part of the field in a bundle. The protofilaments are clearly visible. Some cross-bridges join adjacent microtubules. The neurofilaments are also linked by cross-bridges (x200,000). (With permission from Peters et al., 1991.)

(Alberts et al., 2002). There is ample evidence that axon diameter increases with increasing neurofilament number and with the degree of neurofilament phosphorylation. When neurofilament transport or assembly is prevented, axonal radial growth is much reduced. Phosphorylation induces neurofilaments to extend side arms that increase the filament spacing. Myelination promotes axon radial growth by causing an accumulation of neurofilaments and by induction of neurofilament phosphorylation (Starr et al., 1996; Yin et al., 1998; Jessen and Mirsky, 1999). In that respect, there is evidence that oligodendrocytes control the axonal phenotype in the same way as Schwann cells (Sanchez et al., 1996).

The microtrabecular matrix, which can be visualized with special techniques, is a network cross-linking neurofilaments, microtubules and membranous organelles (Fig. 3; Hirokawa, 1982; Schnapp and Reese, 1982; Hirokawa et al., 1984; Langford et al., 1987; Ichimura and Ellisman, 1991). Vesiculotubular membranous profiles act as transport vectors for newly synthesized protein and lipid and tend to accumulate proximal to a transport blockage (Ellisman et al., 1984). Finally the axon contains a few lamellated bodies and multivesicular bodies and various electron dense granules (Berthold and Rydmark, 1995).

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