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PubMedDate not supplied

Changes in cytoskeletal protein synthesis following axon injury and during axon regeneration.

Injury to the axons of facial motoneurons stimulates increases in the synthesis of actin, tubulins, and GAP-43, and decreases in the synthesis of neurofilament proteins: mRNA levels change correspondingly. In contrast to this robust response of peripheral neurons to axotomy, injured central nervous system neurons show either an attenuated response that is subsequently aborted (rubrospinal neurons) or overall decreases in cytoskeletal protein mRNA expression (corticospinal and retinal ganglion neurons). There is evidence that these changes in synthesis are regulated by a variety of factors, including loss of endoneurially or target-derived trophic factors, positive signals arising from the site of injury, changes in the intraaxonal turnover of proteins, and substitution of target-derived trophic support by factors produced by glial cells. It is concluded that there is, as yet, no coherent explanation for the upregulation or downregulation of any of the cytoskeletal proteins following axotomy or during regeneration. In considering the relevance of these changes in cytoskeletal protein synthesis to regeneration, it is emphasized that they are unlikely to be involved in the initial outgrowth of the injured axons, both because transit times between cell body and injury site are too long, and because sprouting can occur in isolated axons. Injury-induced acceleration of the axonal transport of tubulin and actin in the proximal axon is likely to be more important in providing the cytoskeletal protein required for initial axonal outgrowth. Subsequently, the increased synthesis and transport velocity for actin and tubulin increase the delivery of these proteins to support the increased volume of the maturing regenerating axons. Reduction in neurofilament synthesis and changes in neurofilament phosphorylation may permit the increased transport velocity of the other cytoskeletal proteins. There is little direct evidence that alterations in cytoskeletal protein synthesis are necessary for successful regeneration, nor are they sufficient in the absence of a supportive environment. Nevertheless, the correlation that exists between a robust cell body response and successful regeneration suggests that an understanding of the regulation of cytoskeletal protein synthesis following axon injury must be a part of any successful strategy to improve the regenerative capacity of the central nervous system.

Actins↗

PubMed1981

'Acrylamide-induced' neuropathy and impairment of axonal transport of proteins. I. Multifocal retention of fast transported proteins at the periphery of axons as revealed by light microscope radioautography.

The axonal transport of proteins was studied in ciliary ganglia of control and acrylamide-treated chickens. After an intracerebral injection of [3H]lysine, the distribution of axonally transported proteins was analyzed in the preterminal segments of preganglionic axons and in their caliciform nerve endings by means of quantitative light microscope radioautography. By 7 days after the injection of [3H]lysine, the concentration of labeled proteins in the preganglionic axons was either similar or slightly increased in acrylamide-treated chickens as compared to controls. In contrast, by 3 h, whereas the axons of controls were poorly radioactive, 20-30% of the axons in acrylamide-treated chickens displayed focal and intense labeling at their periphery; simultaneously, in acrylamide treated chickens, 20-30% of the nerve endings contained a decreased amount of radioactive proteins. It is concluded that acrylamide induces multifocal retention of fast axonally transported proteins in preterminal segments of certain axons.

Acrylamides↗

PubMed1992

Horseradish peroxidase labeling of growth cones and axons beyond the site of injury in injured rabbit optic nerve axons growing in their own environment.

Spontaneous growth of injured axons in the mammalian central nervous system is limited. We have previously shown an apparently regenerative growth of injured optic axons in the adult rabbit, achieved by supplying them with soluble substances originating from growing axons, followed by low energy helium-neon laser irradiation. The growing unmyelinated and thinly myelinated axons were embedded in astrocytes, and some were in the process of remyelination by oligodendrocytes. They were shown to have originated from the retinal ganglion cells. The present study further supports evidence relating to the origin and nature of these axons. Light microscopic analysis of these axons labeled with anterogradely transported horseradish peroxidase revealed that many of these axons have varicosities and bear growth cone-like swellings in their tips. These axons traverse the lesion site and extend into the distal stump in a disorganized pattern.

Animals↗

PubMed1993

GABA-immunoreactive profiles provide synaptic input to the soma, axon hillock, and axon initial segment of ganglion cells in primate retina.

GABA-immunoreactive displaced amacrines were previously shown to make synapses onto neuronal profiles in the ganglion cell layer (GCL) of macaque monkey retina [Koontz, Hendrickson and Ryan (1989) Visual Neuroscience, 2, 19-25]. These postsynaptic elements have been investigated further using postembedding immunogold methods for electron microscopy. This paper provides ultrastructural evidence that GABA-immunoreactive profiles are presynaptic to the ganglion cell soma, axon hillock, and axon initial segment in the GCL and its border with the nerve fiber layer (NFL). Some axonal profiles have a dense undercoat and fasciculated microtubules, features that are characteristic of the axon initial segment in many neurons of both central and peripheral nervous systems. These features are confined to small- and medium-diameter (0.2-0.6 microns) axon profiles located near the GCL/NFL border and are not found on axonal profiles lying deep in the NFL, suggesting that the dense-coated region does not extend far along the axon and that the dense-coated region may be narrower than the distal part of the axon. The dense-coated region may correspond to the ganglion cell "narrow segment" recently described in a variety of species using light microscopic methods. The results presented here strengthen our previous hypothesis that GABA-immunoreactive neurons in the GCL provide direct synaptic input to ganglion cells near the site of action potential initiation.

Aged↗

PubMed1985

Fast axonal transport of membrane protein and intra-axonal diffusion of free leucine in a neuron of Aplysia.

We injected radioactive leucine into a neuron soma of Aplysia, and found that the leucine and synthesized membrane proteins moved in the axon, but soluble proteins did not. The movement of membrane proteins showed typical characteristics of fast axonal transport, whereas that of leucine could be explained totally due to intra-axonal diffusion by the following observations: the migration profiles of the leucine closely coincided with the theoretical diffusion; the migration continued even when the fast axonal transport of membrane proteins was stopped by local cooling of the axon; and a damming phenomenon, an indication of axonal transport, seen in membrane proteins was not observed when the axon was occluded or when the axonal transport was blocked by the local cooling.

Animals↗

PubMed1995

Axons from the olfactory bulb transplanted into the hippocampal formation show axon preferences and form transplant-to-host synapses similar to those of normal afferents.

Using a mouse Thy-1 allelic system (an AKR strain of Thy-1.1 was used as the host and a BALB/c strain of Thy-1.2 as the graft), characteristics of transplant-to-host axon projection and synapse formation of the olfactory bulb (OB) were studied in the hippocampal formation by immunohistochemical and ultrastructural examinations. Thy-1.2-positive axon projections were most prominent in the dentate molecular layer (DM), although there was a labeled-axon-poor layer in the innermost part of the DM. Some of the axons in the DM entered the hippocampus proper, forming two clear borders between the two axon-rich outer layers and the inner axon-poor central layer. These results suggested that axons from the transplanted OB extended into the hippocampal formation, showing axon preferences. In the ultramicroscopic observation of the DM, three different synaptic patterns could be distinguished among the transplant-to-host synapses. These three synaptic patterns are similar to those of the synapses formed by perforant path fiber terminals in the DM, indicating that the transplanted OB forms fiber connections with the dendrites of the dentate granule neurons similar to those of normal afferents.

Animals↗

PubMed1988

Cortical axons branch to multiple subcortical targets by interstitial axon budding: implications for target recognition and "waiting periods".

We are studying how axons branch in vivo. Individual cortical neurons send axons to both the spinal cord and the basilar pons. Here we show that the corticopontine projection develops by an interstitial budding of collaterals from parent axons rather than a reported mechanism of axon branching, growth cone bifurcation. This mechanism is used regardless of whether the parent axon's postpontine segment, which forms the corticospinal projection, is permanent (motor cortex) or transient (visual cortex). Budding occurs days after the parent axons grow spinally past the pons, accounting for the "waiting period" reported in this system in contrast to an alternative explanation that the growth cones pause outside of their target. Timing and location of pontine collateral budding vary with cortical origin of the parent axon and are correlated with the temporal ordering of axon arrival.

Animals↗

PubMed2005

Apoptosis is secondary to non-apoptotic axonal degeneration in neurons exposed to Abeta in distal axons.

The goal of this study was to assess if neurons exposed to amyloid-beta peptide (Abeta) exclusively in distal axons, undergo apoptosis. This is relevant to the loss of cholinergic neurons in Alzheimer's disease. Using a three-compartmented culture system for rat sympathetic neurons, we demonstrate that exposure of axons to Abeta1-42 activates an independent destruction program in axons, which leads to nuclear apoptosis. Abeta-induced axonal degeneration does not involve local caspase activation, but causes caspase activation in cell bodies. Accordingly, inhibition of caspase activation blocks Abeta-induced apoptosis but not axonal degeneration. In agreement with previous suggestions that disruption of nerve growth factor (NGF)-mediated signaling might contribute to the loss of cholinergic neurons, we found that provision of NGF to cell bodies protects sympathetic neurons from Abeta-induced apoptosis. However, our data indicate that Abeta-induced axonal degeneration follows a mechanism different than that activated by NGF withdrawal. Only Abeta-induced axonal degeneration is prevented by the calpain inhibitor calpastatin and is insensitive to the inhibitor of the ubiquitin-proteasome system MG132. Importantly, inhibition of Abeta-induced axonal degeneration by calpastatin prevents nuclear apoptosis.

Amyloid beta-Peptides↗

PubMed2005

High EphA3 expressing ophthalmic trigeminal sensory axons are sensitive to ephrin-A5-Fc: implications for lobe specific axon guidance.

The ophthalmic, maxillary and mandibular axon branches of the trigeminal ganglion provide cutaneous sensory innervation to the vertebrate face. In the chick embryo, the trigeminal ganglion is bilobed, with ophthalmic axons projecting from the ophthalmic lobe, while maxillary and mandibular projections emerge from the maxillomandibular lobe. To date, target tissue specific guidance cues that discriminately guide the axon projections from the two trigeminal ganglion lobes are unknown. EphA receptor tyrosine kinases and ephrin-A ligands are excellent candidates for this process as they are known to mediate axon guidance in the developing nervous system. Accordingly, the expression of EphAs and ephrin-As was investigated at stages 13, 15, 20 of chick embryogenesis when peripheral axons from the trigeminal ganglion are pathfinding. EphA3 is expressed highly in the ophthalmic trigeminal ganglion lobe neurons in comparison to maxillomandibular trigeminal ganglion lobe neurons. Furthermore, from stages 13-20 ephrin-A2 and ephrin-A5 ligands are only localized to the mesenchyme of the first branchial arch (maxillary and mandibular processes), the target fields for maxillomandibular trigeminal ganglion axons. We found that ophthalmic and not maxillomandibular lobe axons were responsive to ephrin-A5-Fc utilizing a substratum choice assay. The implication of these results is that EphA3 forward signaling in ophthalmic sensory axons may be an important mechanism in vivo for lobe specific guidance of trigeminal ganglion ophthalmic projections.

Animals↗

PubMed1996

Changes in the isotype composition of beta-tubulin delivered to regenerating sensory axons by slow axonal transport.

beta-Tubulin is encoded by a family of genes that produces at least five distinct polypeptide isotypes in neurons. Two of these isotypes (i.e., classes II and III) preferentially accumulate in axons, and the expression of one of them (i.e., class II) correlates closely with axonal outgrowth during development and regeneration. In dorsal root ganglion (DRG) neurons, expression of the class II isotype declines to relatively low levels during early postnatal development, and increases dramatically in mature neurons during axon regeneration (i.e., to a level comparable to that in developing neurons). In contrast, expression of the class III isotype, which rises slightly during postnatal development, increases much less than the class II isotype during regeneration. We now document that these changes in gene expression are associated with an increase in the relative amount of class II as compared to class III beta-tubulin delivered to regenerating sensory axons of rat sciatic nerve by slow axonal transport. In this study, the tubulin transported in sensory axons was labeled by injecting [35S]methionine into the L5 DRG either 7 or 14 days after crushing the sciatic nerve; pulse-labeled class II and class III beta-tubulin were identified using immunoprecipitation. This change in the isotype composition of beta-tubulin transported in regenerating axons may influence outgrowth by altering the assembly and dynamic properties of axonal microtubules.

Animals↗

PubMed1999

Involvement of axonal phospholipase A2 activity in the outgrowth of adult mouse sensory axons in vitro.

The effect on axonal outgrowth of inhibition of phospholipase A2 activity was studied in a recently developed in vitro model, where dorsal root ganglia with attached spinal roots and nerve stumps from young adult mice were cultured in an extracellular matrix material (Matrigel). The phospholipase A2 inhibitors 4-bromophenacyl bromide and oleyloxyethyl phosphorylcholine dose-dependently reduced axonal outgrowth from the sciatic nerve stump. A similar inhibitory effect was seen when only the cut nerve end was exposed to the inhibitors in a compartmental culture system. The local effect of phospholipase A2 inhibition was further investigated on axons established in culture, using time-lapse recording. Exposure to phospholipase A2 inhibitors caused the retraction of filopodia extensions and a reduction in growth cone motility within a few minutes. After removal of inhibition, normal growth cone motility and axonal growth were regained. Nerve cell bodies and axons, in contrast to Schwann cells, showed immunoreactivity after staining with an antiserum against secretory phospholipase A2, and elevated levels of the enzyme could be detected after culture for 24 h. The immunoreactive protein was of approximately 170,000 molecular weight (phospholipase A2-170) as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and immunoblotting. The localization of phospholipase A2-170 in axons growing into the Matrigel was also demonstrated by use of a whole-mount technique. The results of this study show the importance of continuous phospholipase A2 activity for growth cone motility and axonal outgrowth in the mammalian peripheral nerve, and suggest the involvement of an axonally localized enzyme.

Acetophenones↗

PubMed1999

Heterophilic binding of L1 on unmyelinated sensory axons mediates Schwann cell adhesion and is required for axonal survival.

This study investigated the function of the adhesion molecule L1 in unmyelinated fibers of the peripheral nervous system (PNS) by analysis of L1- deficient mice. We demonstrate that L1 is present on axons and Schwann cells of sensory unmyelinated fibers, but only on Schwann cells of sympathetic unmyelinated fibers. In L1-deficient sensory nerves, Schwann cells formed but failed to retain normal axonal ensheathment. L1-deficient mice had reduced sensory function and loss of unmyelinated axons, while sympathetic unmyelinated axons appeared normal. In nerve transplant studies, loss of axonal-L1, but not Schwann cell-L1, reproduced the L1-deficient phenotype. These data establish that heterophilic axonal-L1 interactions mediate adhesion between unmyelinated sensory axons and Schwann cells, stabilize the polarization of Schwann cell surface membranes, and mediate a trophic effect that assures axonal survival.

Animals↗

PubMed2004

Semaphorin 3A-mediated axon guidance regulates convergence and targeting of P2 odorant receptor axons.

Semaphorins are known to play an important role in axon guidance of vertebrate olfactory sensory neurons to their targets in specific glomeruli of the olfactory bulb (OB). However, it is not clear how semaphorin-mediated guidance contributes to a systematic hierarchy of cues that govern the organization of this system. Because of the putative role that odorant receptor molecules such as P2 could play in establishing appropriate glomerular destinations for growing olfactory axons, we have also determined the spatial organization of P2 glomeruli in semaphorin 3A (Sema3A) mutant mice. First, in the postnatal OB of control and Sema3A(-/-) mice, we analysed the trajectories of olfactory axons that express the Sema3A receptor, neuropilin-1 (npn-1) and the positions of npn-1(+) glomeruli. Sema3A at the ventral OB midline guides npn-1(+) axons to targets in the lateral and medial OB. Absence of Sema3A permits many npn-1 axons to terminate aberrantly in the rostral and ventral OB. Second, in Sema3A(-/-) mice, many P2 axons are abnormally distributed throughout the ventral OB nerve layer and converge in atypical locations compared with littermate controls where P2 axons converge on stereotypically located lateral and medial glomeruli. In addition to their radically altered spatial distribution, P2 glomeruli in Sema3A(-/-) mice are significantly smaller and more numerous than in heterozygote littermates. These data show that Sema3A is an important repulsive olfactory guidance cue that establishes restricted npn-1(+) subcompartments in the olfactory bulb. Furthermore, Sema3A plays a key role in the convergence of axons expressing the odorant receptor P2 onto their appropriate targets.

Animals↗

PubMed2005

The ability of axons to regenerate their growth cones depends on axonal type and age, and is regulated by calcium, cAMP and ERK.

The processes activated at the time of axotomy and leading to the formation of a new growth cone are the first step in regeneration, but are still poorly characterized. We investigated this event in an in vitro model of axotomy performed on dorsal root ganglia and retinal explants. We observed that the dorsal root ganglion axons and retinal ganglion cell axons, which had grown out on a poly d-lysine/laminin substrate at the time of culture preparation greatly differed in their regenerative response after a subsequent in vitro lesion made far from the cell body. The majority of axons of adult dorsal root ganglia but only a small percentage of axons of adult retinal ganglion cells regenerated new growth cones within four hours after in vitro axotomy, though both kinds of axons were growing before the lesion. The depletion of extracellular calcium and the inhibition of extracellular-signal regulated kinase 1,2 (ERK) and protein kinase A (PKA) at the time of injury significantly impaired the capacity of dorsal root ganglia axons to re-initiate growth cones without affecting growth cone motility. Pharmacological treatments directed at increasing the level of cAMP promoted growth cone regeneration in adult retinal ganglion cell axons in spite of the low regenerative potential exhibited in normal conditions. Understanding the cellular mechanisms activated at the time of lesion and leading to the formation of a new growth cone is necessary for devising treatments aimed at enhancing the regenerative response of injured axons.

Actins↗

PubMed1978

A morphological study of the axons and recurrent axon collaterals of cat alpha-motoneurones supplying different hind-limb muscles.

1. Intracellular injections with horseradish peroxidasewere performed in cat alpha-motoneurones supplying various hind-limb muscles. 2. Ten alpha-motoneurones from each of the quadriceps, posterior biceps, gastrocnemius-soleus and anterior tibial pools as well as from the pool supplying the short plantar muscles were collected for morphological analysis of the intramedullary axonal systems including the recurrent axon collaterals. 3. The diameter of the alpha-motor axons showed considerable variation within each motoneurone pool, the total range being from 4.6 to 9.0 micrometer. No significant difference in mean axon diameter was obtained between the different pools. 4. All alpha-motoneurones supplying the short plantar muscles and one single alpha-motoneurone supplying the quadriceps muscle lacked collaterals completely, while the remaining motoneurones gave off one to five collaterals. 5. The number of axon collateral outbulgings, interpreted as synaptic boutons, wihch originated from a single alpha-motoneurone showed large variation within each pool that possessed axon collaterals, the total range being from seventeen of 158. The mean number varied from forty-four (quadriceps) to eighty-two (anterior tibial). 6. The axon collateral outbulgings were distributed not only in the Renshaw cell area ventromedial to the main motor nuclei but also in those parts of the motor nuclei which were located in the vicinity of the parent cell bodies. In the rostrocaudal direction, the outbulgings were distributed within a distances of less than 1 mm around the position of the parent cell bodies. 7. Some physiological implications of the lack of axon collaterals from alpha-motoneurones supplying the short plantar muscles were discussed in relation to the functional characteristics of plantar muscles and motor units.

Animals↗

PubMed1997

Spatiotemporal gradients of intra-axonal [Na+] after transection and resealing in lizard peripheral myelinated axons.

1. Post-transection changes in intracellular Na+ ([Na+]i) were measured in lizard peripheral axons ionophoretically injected with the Na(+)-sensitive ratiometric dye, sodium-binding benzofuran isophthalate (SBFI). 2. Following axonal transection in physiological saline [Na+]i increased to more than 100 mM in a region that quickly extended hundreds of micrometers from the transection site. This post-transection increase in [Na+]i was similar when the bath contained 5 microM tetrodotoxin, but was absent in Na(+)-free solution. Depolarization of uncut axons in 50 mM K+ produced little or no elevation of [Na+]i until veratridine was added. These results suggest that the post-transection increase in [Na+]i was due mainly to Na+ entry via the cut end, rather than via depolarization-activated Na+ channels. 3. The spatiotemporal profile of the post-transection increase in [Na+]i could be accounted for by movement of Na+ from the cut end with an apparent diffusion coefficient of 1.3 x 10(-5) cm2 s-1. 4. [Na+]i began to decline toward resting levels by 20 +/- 15 min (mean +/- S.D.) post-transection, except in regions of the axon within 160 +/- 85 microns of the transection site, where [Na+]i remained high. The boundary between axonal regions in which [Na+]i did or did not recover probably defines a locus of resealing of the axonal membrane. 5. [Na+]i returned to resting values within about 1 h after resealing, even in axonal regions where the normal transmembrane [Na+] gradient had completely dissipated. The recovery of [Na+]i was faster and reached lower levels than expected by diffusional redistribution of Na+ along the axon. Partial recovery occurred even in an isolated internode, indicating that the internodal axolemma can actively extrude Na+.

Animals↗

PubMed2003

Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo.

Axonal degeneration within the spinal cord contributes substantially to neurological disability in multiple sclerosis (MS). Thus neuroprotective therapies that preserve axons, so that they maintain their integrity and continue to function, might be expected to result in improved neurological outcome. Sodium channels are known to provide a route for sodium influx that can drive calcium influx, via reverse operation of the Na+/Ca2+ exchanger, after injury to axons within the CNS, and sodium channel blockers have been shown to protect CNS axons from degeneration after experimental anoxic, traumatic, and nitric oxide (NO)-induced injury. In this study, we asked whether phenytoin, which is known to block sodium channels, can protect spinal cord axons from degeneration in mice with experimental allergic encephalomyelitis (EAE), which display substantial axonal degeneration and clinical paralysis. We demonstrate that the loss of dorsal corticospinal tract (63%) and dorsal column (cuneate fasciculus; 43%) axons in EAE is significantly ameliorated (corticospinal tract: 28%; cuneate fasciculus: 17%) by treatment with phenytoin. Spinal cord compound action potentials (CAP) were significantly attenuated in untreated EAE, whereas spinal cords from phenytoin-treated EAE had robust CAPs, similar to those from phenytoin-treated control mice. Clinical scores in phenytoin-treated EAE at 28 days were significantly improved (1.5, i.e., minor righting reflex abnormalities) compared with untreated EAE (3.8, i.e., near-complete hindlimb paralysis). Our results demonstrate that phenytoin has a protective effect in vivo on spinal cord axons, preventing their degeneration, maintaining their ability to conduct action potentials, and improving clinical status in a model of neuroinflammation.

Animals↗

PubMed1975

Proportion of muscles spindles supplied by skeletofusimotor axons (beta-axons) in peroneus brevis muscle of the cat.

Of 32 cat peroneus brevis spindles, 23 (72%) were found to be supplied by a least 1 skeletofusimotor or beta-axon. A motor axon was identified as skeletofusimotor when repetitive stimulation of it elicited both the contraction of extrafusal muscle fibers and as acceleration of the discharge of primary ending, which persisted after selective block of the neuromuscular junctions of extrafusal muscle fibers. The block was obtained by stimulating single axons at 400-500/s for a few seconds. Of 135 axons supplying extrafusal muscle fibers, 24 (18%) were shown to be beta-axons; 22 beta-axons had conduction velocities ranging from 45 to 75 m/s. All but three beta-axons increased the dynamic sensitivity of primary endings. Beta-innervated spindles may also be supplied by dynamic gamma-axons.

Animals↗