Gen. Pharmac.,

1976, Vol,

7, pp.

387 to 393. Pergamon

Press. Printed in Great Britain

MINIREVIEW AXONAL TRANSPORT M. A. BISBY Division of Medical Physiology, University of Calgary, Calgary, Alberta, Canada

(Received 25 May 1976)

INTRODUCTION IMAGINE a scale model of a human motoneuron whose axon innervates muscle fibres in the lower leg. The cell body (soma) is the size of a tennis-ball, with dendrites up to two metres in length radiating from it. The axon is a cable about as thick as your thumb, and with a good pair of binoculars you can just see the axon terminals situated two kilometres distant. Combine this remarkable geometry of the neuron with the fact that the soma synthesizes nearly all the macromolecules required by the neuron (Droz & Koenig, 1969R) and you have a cell with problems of communication, maintenance, and distribution of materials. These functions are accomplished by axonal transport, a phenomenon predicted from investigations into the results of axotomy (e.g. Scott, 1906) long before it was first described by Weiss & Hiscoe (1948), and subsequently found to be a universal property of neurons. In this short review of axonal (axoplasmic) transport, I have only cited recent or particularly significant original papers, and in many cases I have mentioned only the most recent paper, since it will direct the interested reader to the relevant earlier work. References to other, more extensive reviews are indicated by the letter R in the text.

vestigation of retrograde transport (see below) the tracers used have been exogenous proteins which can be detected histologically in somata after application to the axon terminals. Labeling of terminals or somata by orthograde or retrograde axonal transport has provided neuroanatomists with revolutionary new techniques for mapping axonal projections in the CNS (Lasek, 1975R). (ii) Nerve crushes Transport is interrupted by damage to the axons, so that the accumulation of materials adjacent to a crush can be used as an indication of transport. This technique has been used to investigate the "steadystate" transport of endogenous organelles, enzymes

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METHODS

Axonal transport of macromolecules and subcellular organelles has been studied using three basic techniques: (i) Tracers After administration of isotopically labeled precursors to neuron somata, labeled macromolecules appear in the axons, and their movement can be followed by examining profiles of radioactivity in nerve trunks at various time intervals after isotope administration (Fig. 1). This technique has been used extensively to study the velocity, metabolic requirements and developmental aspects of axonal tr.ansport (Ochs, 1974R). An alternative is to observe the time-course of arrival of tracers at the axon terminals. In the in-

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8 I0 12 14 16 18 20 22 Cm Fig. 1. Profiles of protein bound 3H-activity in garfish olfactory nerve at intervals after administering 3H-L-leucine to the olfactory mucosa. The velocity of transport, estimated by plotting wavefront position against time, was 222 ram/day at 23°C (Gross & Beidler, 1973.) 387

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and neurotransmitters. An important development is Brimijoin's "Stop-Flow" method, where local cooling of the axon interrupts transport, but on rewarming transport resumes (Brimijoin & Helland, 1976). (iii) Direct observation Direct observation of moving particles in living axons, isolated or in tissue culture has yielded intriguing results on the mechanisms of transport (Cooper & Smith, 1974; Breuer et al., 1975). Unfortunately, only the largest particles can be resolved, and their mode of movement may be atypical.

SYNTHESIS AND TRANSPORT

To facilitate discussion of axonal transport I will consider principally the transport of labeled protein, as it is the best-studied example. Transport of other materials will be mentioned where appropriate. Within 30-50 rain after administration of labeled amino-acid precursors to the neuron soma, labeled proteins appear in the axon (Bisby, 1976a). Protein synthesis inhibitors have no effect on transport of labeled protein if given more than 20 min after precursor: the protein has already been synthesized and subsequent transport is not affected by these agents (Ochs et al., 1970). Protein synthesis occurs in polyribosomes associated with rough endoplasmic reticulum, from where some proteins may be transferred to the Golgi apparatus and undergo glycosylation. Proteins and glycoproteins are then attached to the transport mechanism and released into the axon (Droz, 1975R). Not all the labeled protein is released immediately. Some is sequestered in the soma and slowly released over a period of several days (Cancal o n & Beidler, 1975; McLean et al., 1976). Protein is transported along the axon at a variety of velocities: "fast" transport, up to 400 mm/day at 37°C, and "slow" transport, 1 10 mm/day, are generally accepted as two different phases of transport. Fast transport is considered to be a low-capacity selective process involving predominantly membranebound protein, with the types of protein transported perhaps being related to the function of the axon (Anderson & McClure, 1973). The velocity of fast transport is a constant for all neuron types. Slow transport may represent a "bulk flow" of axoplasm, involving large quantities of soluble protein. Slowly transported proteins include the major structural components of the axon, and are the same for axons with different functions (Hoffman & Lasek, 1975). The rate of axonal regeneration is about the same as slow transport velocity (Frizell & Sjostrand, 1974), so slow transport might be thought of as a growth or renewal of the axon structure. This duality of transport may only be apparent: intermediate velocities have been described (Jeffrey & Austin, 1973R) and a unitary hypothesis for the mechanism of transport has been proposed (Ochs, 1975aR).

Any satisfactory hypothesis for the mechanism of transport must account for the following facts: (i) different proteins are transported at different velocities (Willard et al., 1974), (ii) fast transport is bidirectional. Endogenous protein initially transported in an "orthograde" fashion into the axon is later returned towards the soma by "retrograde" transport (Sjostrand & Frizell, 1975; Bisby, 1976a) (Fig. 2). Some exogenous proteins are taken up by axon terminals and transported to the soma (LaVail, 1975R). The oppositely-polarized transport systems are selective, for labeled endogenous protein transported in the retrograde direction is different in composition from protein simultaneously transported in the orthograde direction (Abe et al., 1974; Bisby, 1976b). (iii) Fast transport is an active process, stopped by inhibitors of ATP production. (iv) Fast transport is an intrinsic property of the axon, and independent of soma or terminals. Electron-microscopic examination of the axon reveals several longitudinally-oriented structures which might be involved in transport; the plasma membrane, neurotubules, neurofilaments and smooth endoplasmic reticulum (SER). Fast transport appears to involve the SER and microtubules. Endogenous protein transported in an orthograde direction and exogenous protein transported in a retrograde direction are associated with SER profiles (Droz, 1975R;

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isolated distal segments Fig. 2. Orthograde and retrograde transport of endogenous protein. Rat sciatic nerves were crushed at intervals after injection or precursor leucine into the ventral horn of the lumbosacral spinal cord, and labeled protein allowed to accumulate for 3 hr. At short intervals after injection there was considerable accumulation at the proximal crush, representing orthograde accumulation. At later times the distal accumulation increased, indicating an increase in retrograde transport. Vertical axis is activity of nerve segments in cpm/mm of nerve. Numbers to the right of each set of columns represents the time (hr) after injection when crush was made (Bisby, 1976a).

Axonal transport Nauta et al., 1975), while slowly transported protein is diffusely located in the axoplasm. Enzymes, such as acetylcholinesterase, which are associated with SER are transported at fast velocities, while soluble enzymes (e.g. choline acetyltransferase) are transported at slow velocities (Tucek, 1975). Large quantities of SER accumulate adjacent to a nerve crush along with other transported organelles such as mitochondria and synaptic vesicles (Droz, 1975R). Drugs which block transport, such as the antimitotic drugs colchicine and vinblastine, and the local anesthetic lidocaine, often destroy microtubules. Of course, the blocking effect of these drugs could be exerted on other structures, but the impulse blocking effect of lidocaine exerted on the plasma membrane occurs at a lower concentration than that required to block transport and de-polymerize microtubules (Byers et al., 1973). The use of analogues of colchicine has demonstrated that their ability to block transport is directly related to their affinity for microtubule protein (Paulson & McClure, 1975). Other circumstantial evidence implicating microtubules is the correlation between microtubule density and transport flux (Smith, 1973; Grainger & Sloper, 1974) and the crossbridges linking microtubules to transported organelles such as synaptic vesicles and mitochondria (Smith et al., 1975). Microtubule protein itself is transported at a slow, rather than fast velocity, but this may represent an exchange of microtubule subunits, rather than a "bulk flow" of microtubules (Davison, 1975). We have now arrived at a hypothesis that microtubules form stationary guides or tracks along which the transported materials move, while the SER seems to be the main form of fast-transported material, containing membrane-bound proteins in its walls, and possibly, soluble protein in its lumen. Other organelles (synaptic vesicles and mitochondria) can also follow the microtubular guide. The actual translocation of materials may depend on a type of "sliding-filament" interaction between microtubules and transported particles, resulting in cross-bridge deformation and ATP hydrolysis, analogous to the actin/ myosin interaction in skeletal muscle. The affinity between microtubules and mitochondria may be of importance not only for the translocation of mitochondria, but also for supplying ATP to the transport system. The analogy with muscle contraction is not entirely satisfactory. Actin-like proteins in nerve cells are associated with microfilaments, rather than microtubules (LeBeaux & Willemot, 1975), and a Ca 2÷activated myosin-like ATPase in axon terminals is associated with synaptic vesicles (Berl et al., 1973). Calcium ions are not required to maintain transport in the axon, though they are involved in loading protein for transport in the soma (Hammerschlag et al., 1975). Nevertheless, it seems a priori likely that the contractile-type proteins are involved in mobile processes within the neuron. We may be naive in our emphasis on the microtubule's role in transport, and

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the complete transport system may be more complex that we realize. An attraction of the "sliding-filament" hypothesis is that it explains the observed range of velocities on the basis of different affinities of different proteins or particles for the translocation event, with the fastest transported materials having the highest affinities. Direct observation of transported particles, probably mitochondria (Cooper & Smith, 1974) and lysosomes (Breuer et al., 1975), shows that they move in a saltatory fashion, the velocity of the jumps approximately that of fast transport, but with delays between jumps producing a lower average velocity. In order to explain retrograde transport we must postulate either that there are two sets of axonal microtubules with opposite polarity in the axon, or that the composition of the transported material determines the direction of translocation at each interaction with the microtubules. Mitigating against two sets of microtubules is the evidence that microtubule assembly is unidirectional (Borisy et al., 1974; Dentler et al., 1974) and that there is a slow orthograde transport of microtubule protein. We have as yet no hypothesis to explain the somal loading or the unloading of transported protein at an appropriate destination. The mechanism of slow transport also remains a mystery, largely because of the difficulty of studying the phenomenon over a time-course of days rather than hours. DESTINATION Autoradiographic studies have shown a preferential labelling of axon terminals by fast transported protein, which is localized in the synaptic vesicles and presynaptic membrane (Droz, 1975R). Microtubules extend into the axon terminals and terminate at the presynaptic membrane (Gray, 1975). Slow transported protein is localized in the axoplasm and terminal mitochondria, and the pre-terminal axon is also heavily labeled. These autoradiographic studies may give rise to the misconception that the axon behaves as a passive pipeline for fast-transported protein. In fact, in a long axon only a fraction of the fast-transported protein leaving the soma reaches the terminals (Cancalon & Beidler, 1975), and the majority is given up to the axon (Ochs, 1975b). This axonal protein is localized in sub-axolemmal cisternae of the SER, and may later appear in the axolemma (Droz, 1975R) or be secreted from the axon (Somogyi et al., 1975) or be incorporated into the myelin sheath (Monticone & Elam, 1975). The ultimate fate of transported protein is largely unknown. There are two-classes of half-lives determined by autoradiography for axonal and terminal protein; rapidly turning-over (and presumably rapidly transported) proteins with a half-life of less than 24 hr, and slowly turning-over protein with half-lives of 10-40 days. The turnover of proteins represents losses through these possible mechanisms (Droz, 1973R): (i) degradation by axonal and terminal proteolytic

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enzymes; (ii) loss of soluble synaptic vesicle protein in association with exocytosis of transmitter, or release of protein from SER cisternae, as demonstrated for acetylcholinesterase (Somogyi et al., 1975); (iii) return of protein to the soma by retrograde transport. In motoneurons 50% of the labeled protein originally transported into the axon is later returned to the cell body (Bisby, 1976a). The relative importance of the other two routes is unknown, and we are far from being able to construct a "balance sheet" for input and output of axonal protein.

FUNCTIONS

The importance of orthograde transport can be simply demonstrated by obstructing transport, mechanically by a crush, or pharmacologically with colchicine. There follows terminal transmission failure, terminal and axonal (Wallerian) degeneration and the phagocytosis of the axon by Schwann cells. The time-course of transmission failure depends on the length of the isolated axon, showing that factors essential for transmission are transported along the axon at a fast velocity (Miledi & Slater, 1970). Wallerian degeneration occurs in a proximo-distal fashion, again suggesting that there is normally axonal transport of a factor ensuring immunity from Schwann cell attack (Joseph, 1973). Clearly orthograde transport conveys substances required for neurotransmission, maintenance of structure and defence. Section of nerve axons frequently produces changes in the innervated cell. For example, taste buds degenerate after glossopharyngeal nerve section, muscle cells show a variety of degenerative changes after motor nerve section, and in some CNS pathways there is trans-synaptic atrophy of neurons deprived of their afferent input. Axonal transport is implicated in the maintenance of these "trophic" interactions, though in the most studied example of skeletal muscle, controversy rages over whether the trophic regulation is accomplished through nerve impulses or axonally-transported "neurotrophins" (Drachman, 1974R). The case for unknown "neurotrophins" rests on the dependence of the time-course of degenerative changes in muscle on the length of the nerve stump, and on certain similarities between the effects of nerve section and drug-induced transport block (e.g. Max & Albuquerque, 1975). A pre-requisite for a "neurotrophin" is that it should be transferred from the nerve to at least the membrane of the target cell. Transynaptic transfer of transported label has been demonstrated at retinal ganglion cell-lateral geniculate cell synapses (Specht & Grafstein, 1973) and between sensory axons and sensory epithelium (Alvarez & Puschel, 1972), but it remains to be unequivocally demonstrated that the transferred label is associated with the originally transported molecule, rather than a degradation product.

A function of retrograde transport is probably the recycling of protein to the soma. Retrograde transport of horseradish peroxidase (HRP) is enhanced by nerve stimulation, and since HRP is taken up by endocytosis into terminal cisternae which are a stage in the life cycle of the synaptic vesicles, it is probable that degraded synaptic vesicle membrane components are returned to the cell body (Teichberg et al., 1975). Retrograde transport of dopamine-fl-hydroxylase, a constituent of the membranes of adrenergic synaptic vesicles, can also be explained as a recycling of old vesicles (Brimijoin & Helland, 1976). Retrograde transport also has a t r o p h i c role, as shown by the sequence of chromatolytic changes that occur in the soma after axonal transport is interrupted. The potential signals for chromatolysis are numerous (Cragg, 1970R), but the work of Watson (1970) suggests two factors are involved in motoneuron chromatolysis: one is a consequence of loss of functional neurotransmission, the other is a response to axonal injury. Possibly there are neurotrophins originating in the muscle cell that are taken up into the terminals as a consequence of transmitter release and transported to the soma, as occurs for HRP. Anomalous uptake by the axon of exogenous proteins at the site of injury followed by retrograde transport (Kristensson & Olsson, 1975) may signal axonal injury. We have found that there is a rapid reversal of axonal transport at a nerve crush, so that after axonal injury the soma receives larger quantities of retrograde transported endogenous protein than usual: this abnormal feedback from the axon is another candidate for the "signal" (Bisby & Bulger, 1976). The best example of the trophic function of retrograde transport comes from the work of Thoenen and colleagues (Paravicini et al., 1975) who have shown a selective retrograde transport of nerve growth factor (NGF) from adrenergically-innervated tissues to the post ganglionic adrenergic neurons, resulting in induction of a catecholamine-synthesizing enzyme.

CLINICAL SIGNIFICANCE

Once the ubiquity and importance of axonal transport were realized numerous workers investigated the possible involvement of transport disorders in neuropathies or neuromuscular diseases. Many reports show that there are changes in transport in experimental neuropathies (e.g. Schmidt et al., 1975), animal models of human disease (e.g. Bradley & Jaros, 1973) and even neuropathy patients (e.g. Brimijoin et al., 1973) but it is not clear whether the primary disorders are in the transport mechanism itself or in, for example, protein synthesis or energy metabolism which indirectly affect the velocity and flux of transport. Retrograde transport is the mechanism by which some virus particles (e.g. Herpes simplex: Kristensson

Axonal transport

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Fig. 3. Dynamics of axonal transport. (1) Precursors are taken up by the neuron soma and synthesized into protein (2). Protein may be loaded on to the fast transport system after glycosylation via the Golgi apparatus (3), or may be released slowly from a storage site (4). Fast transported protein may be associated with the smooth endoplasmic reticulum (SER) (5). Slow transported material (6) includes microtubule protein (MT), mitochondria (MITO) and axoplasm. Fast transport probably occurs as a result of an energy-requiring interaction between the SER and the microtubules (7). Some fast transported protein is incorporated into the axolemma (8) and may be subsequently transferred to the Schwann cell (9), or secreted from the axon (10). In the terminals axonally transported protein is associated with synaptic vesicles (SV) or the presynaptic membrane (11). Transported protein may be released by exocytosis from SV (12) and may function trophically to regulate the target cell (13). The target cell may synthesize trophic factors which are taken up by the nerve terminals (14) during the terminal recycling of synaptic vesicle membranes (15). The trophic factors and degraded terminal components are returned by retrograde transport (16) to the cell body where they may influence protein synthesis (17). This scheme is partly speculative, and based on figures by Droz (1975R) and Ochs (1975aR). et al., 1971) and neurotoxins (e.g. tetanus toxin: Price et al., 1975) gain access to the CNS. They are taken up by terminals and can be subsequently detected in axons and somata of motor and sensory neurons.

CONCLUSIONS We have come a long way since Weiss and Hiscoes' observations of 1948 in understanding the significance and mechanisms of axonal transport (Fig. 3), but there is still a long way to go. We have an elaborate hypothesis for the mechanism of transport, but to test it we need more rigorous experiments. We have no idea how loading or unloading of transported materials occurs or how the oppositely polarized orthograde and retrograde systems coexist. We are embarrassed by our ignorance of the ultimate fate of transported materials, and we can only speculate about the role of transport in trophic communication. Our knowledge of the functional plasticity of the transport system during the development or regeneration of axons is confused and fragmentary. This catalogue of ignorance is not intended to depress, but to stimulate the use of our present knowledge in formulating better questions for future research.

a selective process involving small quantities of predominantly membrane-bound material; and slow (1-10 ram/day), a growth-type process involving large quantities of material including the major constituents of the axon. While little is known about slow transport, fast transport is an energy-requiring process perhaps involving an interaction between axonal microtubules and smooth endoplasmic reticulum. Fast transport is a bidirectional process. The function of the orthograde component is to supply the asynthetic axon and terminals with materials synthesized in the soma that are required for maintenance of neurotransmission and structural integrity. Retrograde transport may be involved in a recycling of "used" axonal constituents. In addition, both orthograde and retrograde transport are involved in trophic communication between neuron and target cell, manifested as transynaptic changes and chromatolysis of the neuron soma following interruption of transport. There is some evidence that disorders of transport accompany certain disease states. Current ideas about the dynamics of transport are shown in Fig. 3. Acknowledgement--The author's work described in this review has been financed by the Medical Research Council of Canada.

SUMMARY

REFERENCES

Axonal transport of macromolecules and organelles is a universal property of neurons. Two classes of transport have been described: fast (400 mm/day),

ABE T., HAGA T. & KUROKAWAM. (1974) Retrograde axoplasmic transport: its continuation as anterograde transport. FEBS Lett. 47, 272-275.

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ALVAREZJ. & PUSCHELM. (1972) Transfer of material from efferent axons to sensory epithelium in the goldfish vestibular system. Brain Res. 37, 265 278. ANDERSON L. E. & McCLURE W. 0. (1973) Differential transport of protein in axons: comparisons between sciatic nerve and dorsal columns of cats. Proc. natn. Acad. Sci., U.S.A. 70, 1521 1525. BERL S., PUSZKIN W. & NICKLASJ. (1973) Actomyosin-like protein in brain. Science 179, 441446. BISI3Y M. A. (1976a) Orthograde and retrograde transport of labeled protein in motoneurons. Expl Neurol. 50, 628-640. BISBY M. A. (1976b) Preliminary characterisation of labeled protein involved in orthograde and retrograde axonal transport in motoneurons. Canada Physiol. 7, 19. BISBY M. A. & BUEGER V. T. (1976) Reversal of axonal transport at nerve crushes. Society for Neuroscience, 6th Annual Meeting, Abstract. BORISY G. G., OLMSTED J. B., MARCUM J. M. & ALLEN C. (1974) Microtubule assembly in vitro. Fedn Proc. Fedn Am. Socs exp. Biol. 32, 167-174. BRADLEY W. G. & JAROS E. (1973) Axoplasmic transport in axonal neuropathies. II. Axoplasmic flow in mice with motor disease and muscular dystrophy. Brain 96, 247 258. BREUER A. C., CHRISTIAN C. N., HENKART M. & NELSON P. G. (1975) Computer analysis of organelle translocation in primary neuronal cultures and continuous cell lines. J. Cell Biol. 65, 502-576. BRIMIJOIN S., CAPEK P. & DYCK P. J. (1977) Axonal transport of dopamine-fl-hydroxylase in human sural nerves in vitro. Science 180, 1295-1297. BRIMIJOIN S. & HEELAND L. (1976) Rapid retrograde transport of dopamine-fl-hydroxylase as examined by the stop-flow technique. Brain Res. 102, 217-228. BYERS M. R., FINK B. R., KENNEDY R. D., M1DDAUGH M. E. & HENDRICKSONA. E. (1973) Effects of lidocaine on axonal morphology, microtubules and rapid transport in rabbit vagus nerve in vitro. J. Neurobiol. 4, 125-143. CANCALON P. & BEIDLER L. M. (1975) Distribution along the axon and into various subcellular fractions of molecules labeled with 3H-leucine and rapidly transported in the garfish olfactory nerve. Brain Res. 89, 225-244. COOPER P. D. & SMITH R. S. (1974) The movement of optically detectable organelles in myelinated axons of Xenopus laevis. J. Physiol. 242, 77 97. CRAGG B. (1970) What is the signal for chromatolysis? Brain Res. 23, 1 21. DAVISON P. F. (1975) Neuronal fibrillar proteins and axoplasmic transport. Brain Res. 100, 73-80. DENTLER W. L., GRANETT S., WITMAN G. B. & ROSENBAUM J. L. (1974) Directionality of brain microtubule assembly in vitro. Proc. Bath. Acad. Sci., U.S.A. 71, 1710-1714. DRACHMANN D. B. (1974) The role of acetylcholine as a neurotrophic transmitter. Ann. N . Y Acad. Sci. 228, 160-175. DROZ B. (1973) Renewal of synaptic proteins. Brain Res. 62, 383-394. DROZ B, (1975) Synthetic machinery and axoplasmic transport: maintenance of neuronal connectivity. In The Nervous System, (Edited by TOWER D. B.), Vol. 1, pp. 111 127. Raven Press, New York. DROZ B. & KOENIG H. L. (1969) Turnover of proteins in axons and nerve endings. Syrup. Int. Soc. Cell Biol. 8, 35-50. FR1ZELL M. & SJOSTRAND J. (1974) The axonal transport

of slowly migrating (3H) leucine labeled proteins and the regeneration rate in regenerating hypoglossal and vagus nerves of the rabbit. Brain Res. 81, 267 283. GRAINGER F. & SLOPER J. C. (1974) Correlation between microtubule number and transport activity of hypothalamo-neurophypophyseal secretory hormone. Cell Tissue Res. 153, 101 113. GROSS G. W. & BEIDLER L. M. (1973) Fast axonal transport in the C-fibres of the garfish olfactory nerve. J. Neurobiol. 4, 413~428. GRAY E. G. (1975) Presynaptic microtubules and their association with synaptic vesicles. Proc. R. Soc. Ser. B. 190, 369-372. HAMMERSCHLAG R., DRAV1D A. R. & CHIU A. Y. (1975) Mechanism ofaxonal transport: a proposed role for calcium ions. Science 188, 273 275. HOFFMAN P. N. & LASEKR. J. (1975) The slow component of axonal transport. Identification of major structural polypeptides of the axon and their generality among mammalian neurons. J. Cell Biol. 66, 351 366. JEFFREY P. L. & AUSTIN L. (1973) Axoplasmic transport. Pro cir. Neurobiol. 2, 205 255. JOSEPH B. S. (1973) Somatofugal events in Wallerian degeneration: a conceptual overview. Brain Res. 59, 1-18. KRISTENSSON K., LYCKE E. 8~ SJOSTRAND J. (1971) Spread of Herpes simplex virus in peripheral nerves. Acta neuropath. 17, 44~53. KRISTENSSON K. & OLSSON Y. (1975) Retrograde transport of horseradish peroxidase in transected axons. II. Relation between rate of transfer from the site of injury to the perikaryon and onset of chromatolysis. J. Neurocytol. 4, 653 661. LASEKR. J. (1975) Axonal transport and the use of intracellular markers in neuroanatomical investigations. Fedn Proc. Fedn Am. Socs exp. Biol. 34, 1603-1611. LAVA1L J. (1975) The retrograde transport method. Fedn Proc. Fedn Am. Socs exp. Biol. 34, 1618 1624. LEBEUX Y. & WILLEMOTJ. (1975) An ultrastructural study of the neurofilaments in rat brain by means of heavy meromyosin labeling. Cell Tissue Res. 160, 1-68. MAX S. R. 8~ ALBUQUERQUE E. X. (1975) Neurotrophic regulation of acetylcholinesterase in regenerating skeletal muscle. Expl Neurol. 49, 852 857. MCLEAN W. G., FRIZELL M. & SJOSTRAND J. "(1976) Labeled protein in rabbit vagus nerve between the fast and slow phases of axonal transport. J. Neurochem. 26, 77 82. MILEDI R. & SLATER C. R. (1970) On the degeneration of the rat neuromuscular junction after nerve section. J. Physiol. 207, 507 528. MONTICONE R. E. & ELAM J. S. (1975) Isolation of axonally transported glycoproteins with goldfish visual system myelin. Brain Res. 100, 61 71. NAUTA H. J. W., RAISERMAN-ABRAMOF L R. & LASEK R. J. (1975) Electron microscopic observations of horse-radish peroxidase transported from the caudoputamen to the substantia nigra in the rat: possible involvement of the agranular reticulum. Brain Res. 85, 373 384. OCHS S. (1974) Axoplasmic transport. In The Peripheral Nervous System, (Edited by HUBBARD J. I.), pp. 47-72. Plenum Press, New York. OCHS S. (1975a) A unitary concept of axoplasmic transport based on the transport filament hypothesis. In Recent Advances in Myology, (Edited by BRADLEYW. G., GAP,D-

Axonal transport NER-MEDWIN D. & WALTON J. N.), pp. 189-194. Excerpta Medica, Amsterdam. OcHs S. (1975b) Retention and redistribution of proteins in mammalian nerve fibres by axoplasmic transport. J. Physiol. 253, 459-476. OcHs S., SAI3RI M. I. & RANISH N. (1970) Somal site of synthesis of fast transported materials in mammalian nerve fibres. J. Neurobiol. 1, 329 344. PAULSON J. C. & McCLURE W. O. (1975) Inhibition of axoplasmic transport by colchicine, podophyllotoxin and vinblastine: an effect on microtubules. Ann. N.E Acad. Sci. 253, 517-534. PARAVICINI V., STOECKEL K. & THOENEN H. (1975) Biological importance of retrograde axonal transport of nerve growth factor in adrenergic neurons. Brain Res. 84, 279-291. PRICE D. L., GRIFFIN J., YOUNG A., PECK K. & STOCKS A. (1975) Tetanus toxin: direct evidence for retrograde intra-axonal transport. Science 188, 945-946• SCHMIDT R. E., MATSCHINSKYF. M., GODFREY D. A., WILLIAMS A. D, 8£ McDOUGAL D. B. (1975) Fast and slow axoplasmic flow in sciatic nerve of diabetic rats. Diabetes 24, 1081-1085. SCOTT F. H. (1906) On the relation of nerve cells to fatigue of their nerve fibres. J. Physiol. 34, 145-162. SJOSTRAND J. & FmZELL M. (1975) Retrograde axonal transport of rapidly ,migrating proteins in peripheral nerves. Brain Res. 85, 325-330.

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SMITH D. S., JARLFORS U. • CAMERON B. F. (1975) Morphological evidence for the participation of microtubules in axonal transport. Ann. N.Y. Acad. Sci. 253, 472-505. SMITH R. S. (1973) Microtubule and neurofilament densities in amphibian spinal root nerve fibres: relationship to axoplasmic transport. Can. J. Physiol. Pharmac. 51, 798 806. SOMOGYI P., CHUBB I. W. & SMITH Ab D. (1975) A possible structural basis for the extracellular release of acetylcholinesterase. Proc. R. Soc. Ser. B, 191,271-283. SPECHT S. & GRAFSTEIN B, (1973) Accumulation of radioactive protein in mouse cerebral cortex after injection of 3H-fucose into the eye. Expl Neurol. 41, 705-722. TUCEK S. (1975) Transport of choline acetyltransferase and acetylcholinesterase in the central stump and isolated segments of a peripheral nerve. Brain Res. 86, 259-270. TE1CHBERG S., HOLTZMANN E., CRAIN S. M. & PETERSON

E. R. (1975) Circulation and turnover of synaptic vesicle membrane in fetal mammalian spinal cord neurons. J. Cell Biol. 67, 215-230. WATSON W. E. (1970) Some metabolic responses of axotomised neurons to contact between their axons and dennervated muscle. J. Physiol. 210, 321-343. WEISS P. & HISCOE H. B. (1948) Experiments on the mechanism of nerve growth. J. exp. Zool. 107, 315-395. WILLARD M., COWAN W. M. ~,~ VAGELOS P. R. (1974) The polypeptide composition of intra-axonally transported proteins: evidence for four transport velocities. Proc. natn. Acad. Sci., U.S.A. 71, 2183-2187.

Axonal transport.

Gen. Pharmac., 1976, Vol, 7, pp. 387 to 393. Pergamon Press. Printed in Great Britain MINIREVIEW AXONAL TRANSPORT M. A. BISBY Division of Medical...
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