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The proximal stump of a predominantly myelinated nerve (sternohyoid) was anastomosed in a tube to the distal stump of a largely unmyelinated nerve (cervical sympathetic) in order to explore the role of the axon in activating Schwann cells to produce myelin. The two nerves were examined after being united for periods between 3 and 15 weeks. At these times, regenerating myelinated and nonmyelinated fibres, originating from the proximal stump, were seen within the original fascicle in the distal stump of the sympathetic trunk. There was a significant (P less than 0.01) increase in the mean number of myelinated fibres in the anastomosed sympathetic nerves from the mean number of myelinated fibres in the normal sympathetic nerve. The histological and ultrastructural features of the anastomosed nerves are described and the differences between the morphology of the intratubal and extratubal regions are highlighted. The results of this study may indicate that the axon instructs the Schwann cell to produce myelin, but before this conclusion is reached, the origin of the myelinating cells has to be determined.

Chronically denervated rat and rabbit tibial nerve distal stumps were studied 3-58 weeks following nerve transection. Schwann cells, macrophages and possibly fibroblasts participated in myelin removal which was largely complete by seven weeks. Degenerating myelinated and unmyelinated fibres developed respectively into circular and flattened columns of Schwann cell processes each delimited by a basal lamina. Schwann cell columns became encircled by fibroblasts and later by cells of perineurial type, underwent shrinkage with time and eventually were replaced by connective tissue. In another experiment, endoneurial tissue was removed from rabbit tibial nerve stumps seven weeks after transection and transplanted between the corneal stroma of the same animal for 2-6 weeks. In this locus, Schwann cells developed a thickened basal lamina and then underwent necrosis. It was concluded that the maintenance of Schwann cells in bands of Büngner is in part dependent on axonal contact and that failure of reinnervation eventually causes the columns of Schwann cells to disappear.

Severance of a peripheral nerve leads to a characteristic series of events in the distal stump, including the dissolution of axons and myelin and the proliferation of Schwann cells within their basal lamina. This study examines the relationship between the spatial-temporal pattern of the induction of the Schwann cell S phase, loss of the structural and functional properties of axolemma, and the clearance of myelin debris in the cat tibial nerve. Nerve transection stimulated a monophasic increase in [3H]thymidine incorporation that peaked at 4 days post-transection throughout an 80-mm length of distal stump. Light microscope autoradiography revealed prominent incorporation into Schwann cells of myelinated fibres. Treatment of distal stumps with mitomycin C at the time of nerve transection greatly retarded thymidine incorporation and clearance of myelin debris, but not the time course of axonal degeneration, decline in the synthesis of the major myelin glycoprotein, P0, or the onset of ovoid formation. Nerve transection also greatly reduced the specific uptake of [3H]saxitoxin (STX), a ligand which binds to voltage-sensitive sodium channels. Binding in the distal stump fell precipitously to 20% of the normal at 4 days post-transection, concurrent with the peak of thymidine incorporation. This low level of binding was maintained for periods of up to 70 days, demonstrating that some STX binds to structures other than axons in denervated distal stumps. Prior treatment with mitomycin C delayed the loss of specific STX binding. In conclusion, these studies suggest that: (a) Schwann cell DNA replication- and/or mitosis regulates other events during Wallerian degeneration, including myelin degeneration, catabolism of P0 and the clearance of sodium channels from nodal axolemma; (b) the decline in P0 synthesis and/or shift to synthesis of less extensively processed P0 is independent of the induction of Schwann cell S phase; and (c) Schwann cells enveloping myelinated axons enter S phase within a 24-h period throughout the entire 80-mm length of distal stump.

This paper describes a surgical method of manipulating feline peripheral nerve regeneration to separate spatially the temporal sequence of events of axon-Schwann cell interaction during nerve fibre formation. The method allows regenerating axons from the peroneal nerve to reinnervate the distal stump of a axon- and myelin-free, Schwann cell-enriched, chronically denervated tibial nerve distal stump. Three zones can be morphologically delineated in the tibial nerve stump after three weeks of reinnervation: (1) a proximal myelinated zone, (2) a more distal, non-myelinated, axon-Schwann cell contact zone, and (3) a distal axon-free Schwann cell non-contact zone. The distal limit of the second zone can be determined accurately by the front of an axonally transported label. The large volume of available tissue makes this method suitable for interdisciplinary studies to elucidate the control of axon elongation, axon growth, and axon-Schwann cell inter-relationships.

A mechanism is postulated and described for the sequestration and phagocytosis of unusual and abnormal axoplasmic organelles by Schwann and oligodendroglial cells. Axonal organelles involved in this process are clear and dense-core vesicles, membrane-bounded dense membranous bodies reminiscent of secondary lysosomes, enlarged mitochondria, glycogen-like granules and glycogen-filled mitochondrial remnants. The process of sequestration of these organelles begins with the formation of a ridge of ensheathing cell adaxonal cytoplasm adjacent to an internally coated region of axolemma. The ridge of adaxonal cytoplasm enlarges to form a thin sheet which indents the axon surface adjacent to the abnormal axonal organelles. The invaginating adaxonal cytoplasmic sheet surrounds the abnormal axonal organelles and segregates them from the remainder of the axon. The cytoplasmic sheet infolds on itself and sequesters groups of axoplasmic organelles to form an interdigitated profile when viewed in cross-section. Electron lucent areas correspond to sequestered axoplasm and electron dense areas to ensheathing cell cytoplasm. The membranes separating axoplasm and ensheathing cell cytoplasm in the interdigitated networks break down allowing the abnormal axoplasmic organelles to be phagocytosed by the ensheathing cell cytoplasm. The process occurs to a limited degree in the normal nervous system at paranodes but is much more developed in pathologic situations where there is early axonal disease. The process is maximally developed in situations where there is centripetal axonal degeneration such as occurs in dying-back toxic disease and in the proximal stump of an amputated nerve.

This study examined the thesis that 2,5-dexanedione (2,5-HD) produces distal (dying-back) axonopathy by direct toxic action on nerve fibers. Single or repeated application of undiluted or 10% 2,5-HD to exposed rat sciatic nerves caused some fibres to develop focal axonal swellings filled with abnormally large numbers of 10 nm neurofilaments. Such changes occurred within four days of application and were especially prominent in equivalently treated nerve segments obtained from animals orally exposed to 0.5% 2,5-HD before surgery. Nerve fibers along the perimeter of tibial nerve fascicles exposed to 2,5-HD or 2,4-hexanedione (2,4-HD), a compound unable to produce systemic neuropathy, underwent non-specific breakdown and Schwann cell necrosis. Nerve fibres located in the centre of such fascicles only developed an hypertrophied paranuclear Schwann cell cytoplasm and did not proliferate intermediate filaments. Saline, hydrochloric acid and 1,6-hexanediol, a water-soluble hexacarbon also lacking systemic neurotoxic properties, produced no intra-fascicular changes when locally applied to the sciatic nerve. It is concluded (1) that 2,5-HD causes a giant axonal swellings by direct toxic action on the nerve fibre, (2) 2,5-HD does not induce a generalized disorder of cytoplasmic intermediate filaments and (3) primary Schwann cell changes produced by locally applied 2,5-HD or 2,4-HD are non-specific and unrelated to the formation of the giant axonal swellings.

Pacinian corpuscles from the hindfeet and mesentery of cats have been examined by light and electron microscopy. The study focuses on the inner core region which houses the single, non-myelinated terminal of the afferent axon. This region of the axon possesses specialized axon processes which enormously increase the surface area of the axolemma. The axon processes are long, branched, filiform structures, containing exclusively ~6 nm microfilaments, and are reminiscent of filopodia on the tips of growth cones of axons and dendrites. These axon processes emanate from the two poles of the elliptical terminal axon, from several sites in the transitional zone, and from the entire surface of the ultraterminal axon, the bulbous, branched, distal extremity of the nerve fibre. Each branch of an axon process articulates with an inner core cell hemilamella except at the distal end of the ultraterminal where axon processes may also approximate the inner edge of the outer core. The base of each axon process contains an elaborate array of organelles including clear and dense-core vesicles of synaptic vesicle size, all enmeshed in ~6 nm microfilaments. The structure and location of the axon processes appear to be eminently suitable for detecting pressure transients transmitted through the outer core of the corpuscle. It is suggested that the mechano-electrical transduction system has, as its morphological substrate, multiple units, each formed by a branched axon process and its specialized basal region. The existence of sympathetic axon terminals abutting the central axon is disputed but the presence of unusual, dense-centred and elongated vesicles within cellular profiles close to the axon is confirmed.