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PubMed2000

Local directional cues control growth polarity of dopaminergic axons along the rostrocaudal axis.

The vertebrate CNS is composed of a variety of longitudinal axonal tracts extending rostrally and caudally. Although recent studies have demonstrated that chemoattraction and chemorepulsion play key roles in axon guidance along the circumferential axis in the neural tube of the vertebrate, mechanisms of axonal elongation along the longitudinal axis, and most importantly, what determines rostrocaudal polarity of axonal growth, remains unknown. Here, we examined the mechanism that guides midbrain dopaminergic axons rostrally, using flat whole-mount preparations of embryonic rat brain both in vivo and in vitro. At embryonic day 11 (E11) and early stage E12, dopaminergic neurons in the ventral midbrain extended short axons dorsally. By middle stage E12, these axons had increased in number, some deflecting rostrally and others caudally. At E13, almost all axons showed rostrally oriented growth heading toward the forebrain targets. In in vitro whole-mount preparations prepared from an E12 embryo and cultured for 24 hr, these axons showed rostrally oriented growth, but when they were forced to grow on substratum of reversed rostrocaudal polarity, they turned abruptly and grew following the polarity of the reversed midbrain substratum. These results suggest that local directional cues in the midbrain guide these axons rostrally and support the idea that substratum-associated polarized cues play an important role in axon guidance along the longitudinal axis.

Animals↗
PubMed2000

Common mechanisms underlying growth cone guidance and axon branching.

During development, growth cones direct growing axons into appropriate targets. However, in some cortical pathways target innervation occurs through the development of collateral branches that extend interstitially from the axon shaft. How do such branches form? Direct observations of living cortical brain slices revealed that growth cones of callosal axons pause for many hours beneath their cortical targets prior to the development of interstitial branches. High resolution imaging of dissociated living cortical neurons for many hours revealed that the growth cone demarcates sites of future axon branching by lengthy pausing behaviors and enlargement of the growth cone. After a new growth cone forms and resumes forward advance, filopodial and lamellipodial remnants of the large paused growth cone are left behind on the axon shaft from which interstitial branches later emerge. To investigate how the cytoskeleton reorganizes at axon branch points, we fluorescently labeled microtubules in living cortical neurons and imaged the behaviors of microtubules during new growth from the axon shaft and the growth cone. In both regions microtubules reorganize into a more plastic form by splaying apart and fragmenting. These shorter microtubules then invade newly developing branches with anterograde and retrograde movements. Although axon branching of dissociated cortical neurons occurs in the absence of targets, application of a target-derived growth factor, FGF-2, greatly enhances branching. Taken together, these results demonstrate that growth cone pausing is closely related to axon branching and suggest that common mechanisms underlie directed axon growth from the terminal growth cone and the axon shaft.

Animals↗
PubMedDate not supplied

[The evidence for primary axonal loss in multiple sclerosis].

INTRODUCTION: At what stage in the pathogenesis of multiple sclerosis (MS) does the damage to axons occur, and why should there be any axon loss at all in what is thought to be principally an axon sparing demyelinating disease? A recently described new technique for investigating axon damage depends for its ability on the immunoreactivity of amiloid precursor protein (APP), which has been shown to be more sensitive than silver stains for detecting damaged axons. DEVELOPMENT: We used APP immunoreactivity as a method to investigate whether axon damage occurs in acute MS lesions. The results of our APP staining showed that the expression of APP in MS lesions is associated with acute MS lesions and the active border of less acute lesions. There was little, if any, APP expression in the chronic lesions. If we accept that the APP staining represents irreversible damage to some axons, the next question is what factors are responsible for mediating damage to axons in MS? Matrix metalloproteinases (MMP) are expressed by macrophages in acute MS lesions and in the active borders of active chronic lesions. The injection of highly-purified MMP into the brain results in demyelination, blood-brain barrier breakdown, and axonal loss. Moreover, the inhibition of the MMP activity reduces the severity of MS-like lesions in experimental models. Thus the properties and distribution of these enzymes make them rational targets for therapeutic intervention. CONCLUSION: Whatever mechanism proves to be responsible for axonal damage in MS, it is clear that this disease should, perhaps, be more appropriately recognized as a primary demyelinating entity with associated primary axonal loss.

Acute Disease↗
PubMed1997

Acrylamide intoxication modifies in vitro responses of peripheral nerve axons to anoxia.

Decreased axolemmal Na+/K(+)-ATPase activity has been considered as a possible mechanism for peripheral nerve axon damage induced by acrylamide (ACR) or 2,5-hexanedione (HD). Reduced activity of this enzyme is also presumed to be the basis of peripheral nerve resistance to ischemia or hypoxia associated with other neuropathies (e.g., diabetes). In the present study, we tested the hypothesis that peripheral nerve of ACR (50 mg/kg/d x 10 d) or HD (400 mg/kg/d x 20 d) exposed rats are resistant to oxygen-limiting conditions as a result of reduced axonal Na+/K(+)-ATPase activity. As an index of resistance, effects of in vitro anoxia on subaxonal concentrations of Na, K and Ca were assessed in isolated segments of tibial nerve from control and neurotoxicant-treated animals. Results show axons from HD rats were not resistant to anoxic challenge; i.e., axons exhibited disrupted elemental composition comparable to anoxic control changes. In contrast, ACR-exposed axons displayed anoxic resistance. Ouabain-exposed tibial axons subjected to anoxic conditions were also resistant, but the corresponding elemental pattern did not resemble that associated with ACR axons. Moreover, ACR axons were capable of maintaining elemental gradients during normoxic exposure which should not be possible if Na+ pump activity is depressed. Considered together, these data are not consistent with a role for diminished Na+/K(+)-ATPase activity in neurotoxicant-induced peripheral axonopathy. We also assessed the ability of ACR- and HD-exposed tibial nerve axons to recover from anoxia. Unlike control fibers which can fully restore normal elemental composition, neurotoxicant-exposed axons were incapable of such restoration. These data suggest the axonal machinery responsible for post-anoxia recovery (e.g., energy metabolism, ion translocation, Ca2+ and free radical buffering) is compromised by ACR or HD intoxication.

Acrylamide↗
PubMed2000

Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients.

Axonal degeneration has been proposed as a cause of irreversible neurological disability in multiple sclerosis (MS) patients. The purpose of this study was to quantify axonal loss in spinal cord lesions from 5 paralyzed (Expanded Disability Status Scale score > or =7.5) MS patients and to determine if axonal number or volume correlated with levels of the neuronal marker N-acetyl aspartate (NAA). Axonal loss in MS lesions ranged from 45 to 84% and averaged 68%. NAA levels were significantly reduced (>50%) in cross sections of spinal cords containing MS lesions. Reduced NAA correlated with reduced axonal numbers within lesion areas. In addition, NAA levels per axonal volume were significantly reduced in demyelinated axons (42%) and in myelinated axons in normal-appearing white matter (30%). The data support axonal loss as a major cause of irreversible neurological disability in paralyzed MS patients and indicate that reduced NAA as measured by magnetic resonance spectroscopy can reflect axonal loss and reduced NAA levels in demyelinated and myelinated axons.

Adult↗
PubMed2001

Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons.

Altered axon-Schwann cell interactions in PNS myelin-deficient Trembler mice result in changed axonal transport rates, neurofilament and microtubule-associated protein phosphorylation, neurofilament density, and microtubule stability. To determine whether PNS and CNS myelination have equivalent effects on axons, neurofilaments, and microtubules in CNS, myelin-deficient shiverer axons were examined. The genetic defect in shiverer is a deletion in the myelin basic protein (MBP) gene, an essential component of CNS myelin. As a result, shiverer mice have little or no compact CNS myelin. Slow axonal transport rates in shiverer CNS axons were significantly increased, in contrast to the slowing in demyelinated PNS nerves. Even more striking were substantial changes in the composition and properties of microtubules in shiverer CNS axons. The density of axonal microtubules is increased, reflecting increased expression of tubulin in shiverer, and the stability of microtubules is drastically reduced in shiverer axons. Shiverer transgenic mice with two copies of a wild-type myelin basic protein transgene have an intermediate level of compact myelin, making it possible to determine whether the actual level of compact myelin is an important regulator of axonal microtubules. Both increased microtubule density and reduced microtubule stability were still observed in transgenic mouse nerves, indicating that signals beyond synaptogenesis and the mere presence of compact myelin are required for normal regulation of the axonal microtubule cytoskeleton.

Animals↗
PubMed2004

Autophagy of neuron axon during regeneration of rat sciatic nerves.

OBJECTIVE: To investigate the autophagic clearance of degenerated neuron axon during regeneration of rat sciatic nerves. METHODS: Wallerian degeneration model was established in rats by sciatic nerve transection. Samples from the distal stump were collected at different time points after the transaction and ultrathin sections prepared for electron microscopic examination and acid phosphatase (AcPase) activity detection. RESULTS: Neuron axon degeneration occurred after transection of rat sciatic nerve, presenting predominantly swelling of the axoplasm and separation of the axon from the myelin sheath seen 5 h to 2 d after the transection. On day 4, axoplasm condensation took place and the axons were completely separated from the myelin sheath to form dissociative axon body. Vacuoles of various sizes were identified in the axon in the early stage after operation and later when the axons were completely dissociated from the nerve sheath, larger dissociative axon bodies occurred. The axolemma surrounding the axon body was derived from the neuronal cytomembrane, and the condensed axoplasm contained numerous autophagic vacuoles at all levels along with large number of neurofilaments, microtubules and microfilaments arranged in a crisscross pattern. The autophagic vacuoles exhibited acid phosphatase (AcPase) activities. Since the day 7, the axon bodies were absorbed after degradation and macrophages could be spotted occasionally. CONCLUSION: The degenerated axons were cleared mainly through autophagy during regeneration of rat sciatic nerve and macrophages only assist in this process.

Actin Cytoskeleton↗
PubMed2005

A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer's disease.

OBJECTIVE: To study the density and cross-sectional area of axons in the optic nerve in elderly control subjects and in cases of Alzheimer's disease (AD) using an image analysis system. METHODS: Sections of optic nerves from control and AD patients were stained with toluidine blue to reveal axon profiles. RESULTS: The density of axons was reduced in both the center and peripheral portions of the optic nerve in AD compared with control patients. Analysis of axons with different cross-sectional areas suggested a specific loss of the smaller sized axons in AD, i.e., those with areas less that 1.99 microm2. An analysis of axons >11 microm2 in cross-sectional area suggested no specific loss of the larger axons in this group of patients. CONCLUSIONS: The data suggest that image analysis provides an accurate and reproducible method of quantifying axons in the optic nerve. In addition, the data suggest that axons are lost throughout the optic nerve with a specific loss of the smaller-sized axons. Loss of the smaller axons may explain the deficits in color vision observed in a significant proportion of patients with AD.

Aged↗
PubMed1991

A target-derived chemoattractant controls the development of the corticopontine projection by a novel mechanism of axon targeting.

Here, we review our studies in rats of target recognition by developing cortical axons focusing on their innervation of the basilar pons, a major hindbrain target. The corticopontine projection develops by a 'delayed interstitial budding' of collaterals from layer 5 corticospinal axons, rather than by a direct ingrowth of primary axons or by bifurcation of the growth cone. Branches form de novo from the axon cylinder in the pathway overlying the basilar pons and extend directly into it. Co-cultures of cortex and basilar pons in 3-dimensional collagen matrices show that a diffusible chemotropic signal released by the basilar pons directs the growth of collateral branches from layer 5 axons in a target and neuron specific manner. 'Delayed' co-cultures suggest that a diffusible, pontine-derived signal also initiates the selective branching of layer 5 axons. In vivo experiments support this chemotropic mechanism. First, corticospinal axons form collateral branches at novel locations directly over ectopic aggregations of basilar pontine neurons induced by X-irradiation; no branches form at positions that would normally overlie the appropriate region of basilar pons which is absent because of the X-irradiation. Thus, the basilar pons, rather than local cues in the axon pathway, appears to control the location of corticospinal axon branching. Second, in a series of experiments in which different subsets of corticospinal axons are prevented from innervating the basilar pons, remaining corticospinal axons extend collaterals in a directed manner to regions of the basilar pons deprived of cortical input, a behavior consistent with a response to a diffusible chemoattractant emanating from these regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Regulation of axonal caliber, neurofilament content, and nuclear localization in mature sensory neurons by nerve growth factor.

The neuronal perikaryal response to axonal injury (axon reaction) includes reduction in axonal caliber beginning in the proximal portion of the nerve (somatofugal axonal atrophy), development of nuclear eccentricity, and chromatolysis. The means by which these events are triggered is unknown, but it has been argued that loss of a neurotrophic signal from the target of injured neurons plays a role. To date, the identity of this substance(s) remains unknown. In the present study, we have asked whether NGF normally functions to control axonal caliber of sensory neurons in the L4 and L5 dorsal root ganglia (DRG) of the adult rat. Two approaches were used: (1) NGF was continuously delivered to the proximal stump of a transected sciatic nerve to determine whether NGF administration would prevent the production of somatofugal axonal atrophy; and (2) NGF antisera were administered to normal animals to determine whether NGF deprivation would produce somatofugal axonal atrophy. In the first experiment, 9-week-old rats underwent a unilateral sciatic nerve transection at midthigh, and the proximal stump was connected to an osmotic pump containing either NGF or cytochrome C (as control). At 11 weeks of age, dorsal root fibers in lumbar DRG from the control group appeared smaller in caliber and less circular in shape than fibers from age-matched normal animals. Although smaller than those in normal animals, fibers from the NGF-treated nerves were larger than in axotomized controls. Mean axonal area and shape factor (an index in circularity) were measured and found to be decreased significantly (22% and 15%, respectively) from the control group. Fibers from the NGF-treated nerves were significantly (p less than 0.05) larger in axonal caliber and more circular in shape; mean values were only reduced by 11% and 10%, respectively. Quantitation of neurofilament (NF) numbers revealed that the larger calibers in the NGF-treated nerves result from a greater NF content. NGF treatment did not prevent the atrophy of motor fibers in the proximal ventral root. In the second experiment, 2 antisera to mouse NGF were given daily into the footpad for 11 or 12 d; control animals were given normal goat serum. Quantitation of axonal calibers in the L5 DRG demonstrated that mean axonal area and shape factor were significantly (p less than 0.05) reduced by 14% and 17% respectively. The axoplasm of atrophic fibers demonstrated a paucity of NFs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Axonal transport and localization of B-50/GAP-43-like immunoreactivity in regenerating sciatic and facial nerves of the rat.

Neurons that can regenerate their axons following axotomy increase their synthesis and axonal transport of a growth-associated protein, called GAP-43, which has been shown to be identical to the synaptic phosphoprotein B-50. The function of B-50/GAP-43 to the process of regeneration is unknown. We used a polyclonal, affinity-purified antibody against B-50 to study the axonal transport and localization of B-50/GAP-43-like immunoreactivity (B50LI) in the regenerating sciatic and facial nerves of adult rats. Quantitative data were obtained by densitometry of the B-50 band in immunoblots of nerve segments, which had been run on SDS-polyacrylamide gels. In the regenerating sciatic nerve, anterograde accumulation at a collection ligature was 3.0 times higher than retrograde accumulation. The mobile fraction of B50LI was only 0.28 of total B50LI and traveled with a mean anterograde velocity of 5.3 mm/hr. B50LI distribution in the newly regenerated portion of the nerve revealed maximal B50LI levels midway between the position of the crush and the fastest-growing axons. Immunocytochemistry of this portion of the nerve demonstrated B50LI to be associated with regenerating axons but also to a large extent with extra-axonal structures outlining the Schwann cell bands of Büngner. This zone of B50LI-positive Schwann cell bands was found to extend more distally in nerves in which regeneration had processed longer, e.g., up to 5 mm distal to the crush after 3 d and 8 mm after 4 d. Further distal to this zone, many fine regenerating axonal profiles could be detected with B-50 antibody, but were neurofilament negative. These findings raise the possibility of an extra-axonal function of B-50/GAP-43, as this protein might be secreted from regenerating axons and might play a role in axon-Schwann cell interactions during axonal maturation.

Animals↗
PubMed1989

A single-cell analysis of early retinal ganglion cell differentiation in Xenopus: from soma to axon tip.

Intracellular injections of Lucifer yellow (LY) were made into the cell bodies of Xenopus retinal ganglion cells from the earliest stages of axonogenesis to the beginning of target innervation. Embryos were intact during the injection so that the entire cell (cell body, dendrites, axon, and growth cone) could be visualized. The purpose of the study was 3-fold: (1) to characterize the early steps in retinal ganglion cell differentiation before the axon reaches its target; (2) to determine whether guidepost cells exist as possible navigation cues in the vertebrate optic pathway; and (3) to investigate whether the morphology of early retinal ganglion cell growth cones varies in a position-dependent manner along the primordial optic pathway. Axons were generally initiated before dendrites and followed a well-defined course along the primordial optic pathway without branching. Surprisingly, at least 5% of the retinal ganglion cells sent more than one axon into the optic pathway. Sister axons from the same parent cell traveled separately in the pathway, indicating that their growth cones navigated independently. Examination of dendrite genesis showed that dendrites usually begin to emerge from the cell body well before the axon tip reaches the target. This observation argues against the possibility that target contact influences dendrite initiation. Nascent dendrites were commonly tipped with pronounced varicosities that did not resemble axon growth cones. Their number and branching correlated well with axon length, indicating that the age of the retinal ganglion cell itself, rather than the age of its presynaptic cells or local environment, is the strongest influence on dendrite genesis. Examination of LY-filled growth cones at varying points in the pathway showed no evidence of dye transfer to adjacent cells. This indicates that gap junctional contacts probably do not form during axonal pathfinding and suggests that direct intercellular communication between growing axons and other cells in the pathway does not play a major role in axon guidance. Growth cone morphology was analyzed quantitatively and found to vary at different positions along the pathway. Growth cones entering the optic nerve head were the largest and most complex; those on the retinal surface were the smallest and showed a simple morphology. Growth cones in the chiasm and optic tract showed a degree of complexity similar to those in the optic nerve head but were smaller.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Effect of changes in neurofilament content on caliber of small axons: the beta,beta'-iminodipropionitrile model.

The structural role of neurofilaments in the normal axon and the consequences of altered axonal transport of neurofilaments have been extensively studied in large axons. These studies suggest that neurofilament numbers and interneurofilament spacing are major determinants of axonal cross-sectional area. In contrast, in small axons and dendrites, microtubules and membranous organelles appear to be the most closely correlated with size and shape of the cell process. In this study we have examined the effect of impairment in neurofilament transport on small axons, typical of most CNS pathways. Neurofilament transport was impaired by administration of beta,beta'-iminodipropionitrile (IDPN), resulting in proximal accumulation and distal depletion of neurofilaments. The evolution of these changes was studied in the optic nerves of guinea pigs treated with IDPN, 1-35 weeks following intoxication. The effect of this redistribution of neurofilaments on cross-sectional area of small axons was evaluated using quantitative ultrastructural methods. Our results show that with the alteration in neurofilament transport seen with IDPN intoxication, there is a wide spectrum of neurofilament densities, ranging from a 5-fold increase above normal in the proximal axon, to a 5-fold decrease below normal in the distal axon. Although the optic nerve fibers enlarge with the increase in neurofilament content, they do not atrophy significantly with the continued loss of neurofilaments. We conclude that factors other than neurofilament content are capable of maintaining size and shape of these small axons. Candidate organelles include microtubules and membranous organelles and possibly other axonal elements.

Animals↗
PubMed1987

Age-related changes in the number of myelinated axons and glial cells in the anterior and posterior limbs of the mouse anterior commissure.

The total number of axons and the number of myelinated axons was estimated in both limbs of the anterior commissure of mouse brains from 5 to 31 months of age. The total number of glial cells and the percentage of each type of glial cell was estimated in both limbs of the anterior commissure at 25, 28 and 31 months since similar estimations had already been carried out in mice aged between 5 and 22 months. The total number of axons and the number of myelinated axons both appeared to fall between 9 and 12 months and to increase again between 22 and 25 months in the anterior limb whereas in the posterior limb the total number of axons remained constant but the number of myelinated axons increased between 22 and 28 months. Two types of abnormality were seen in myelinated fibres at all ages after 12 months. These consisted of degenerating axons enclosed in normal myelin sheaths and apparently normal axons surrounded by vacuolated sheaths. The total number of glial cells in both limbs decreased between 9 and 12 months and increased substantially between 22 and 25 months. There was a statistically significant correlation between the number of oligodendrocytes and the percentage of myelinated axons in both limbs at different ages. There was no change in the very small number of mitotic figures in the anterior commissure to account for the fluctuation in glial number. It is postulated that there is a continuous loss and replacement of myelinated axons in both limbs of the commissure from 12 to 31 months of age and that this is possible since the amount of axon loss is so small that there is no significant phagocytic or astrocytic response. An increased requirement for myelination appears capable of bringing about an increase in the number of oligodendrocytes even in aged animals.

Aging↗
PubMed1983

Monoclonal antibodies demonstrate the organization of axons in the leech.

Monoclonal antibodies have been generated that bind to subsets of neurons within the leech central nervous system (Zipser, B., and R. McKay (1981) Nature 289: 549-554). In this report we describe the binding patterns of monoclonal antibodies to subsets of axons in the leech using HRP-immunohistochemistry. Each antibody has a characteristic staining pattern in the connective, the large bundle of axons that runs the length of the nerve cord connecting each ganglion to its rostral and caudal neighbors. These staining patterns are consistent along the rostrocaudal axis of each animal, between animals of the same species, and, in many cases, between animals of different species. These results show that axonal position, like neuron cell body position, is a consistent feature of the organization of the leech central nervous system. Two antibodies bind to all of the axons in particular fascicles that are delimited by glial cell processes; another binds to single axons in fascicles that contain other, unstained axons. The grouping of antibody-identified axons into fascicles does not correlate in a simple way with the grouping of neuron cell bodies identified with the same antibody. The presence of one of these antigens on the surface of axons suggests a possible role in axon fasciculation. This report shows that molecular heterogeneity is a property of axons as well as of neuron cell bodies and demonstrates the organization of specific antibody-identified groups of axons within the connective.

Animals↗
PubMed1983

Termination of afferent axons in macaque striate cortex.

We used horseradish peroxidase (HRP) to orthogradely label afferent axons in macaque striate cortex. Of the 38 axons that we recovered, nine were recorded intracellularly before being filled with HRP. Light microscope and computer reconstructions of filled processes reveal highly stereotyped patterns of arborization and suggest that there are at least five discrete populations of lateral geniculate nucleus (LGN) afferent axon: (1) those to layer 4C beta, which have extremely circumscribed, dense terminal fields (small branches of which occasionally intrude into 4C alpha) but which have not been shown to project to other laminae; (2) afferents to layer 4A, which in some cases send fine ascending collaterals into layer 2-3 and which do not, apparently, send collaterals to other laminae; (3) afferents to layer 1, which are fine, extend over large distances horizontally, and send collaterals to layer 6A; (4) afferents to the lower two-thirds of layer 4C alpha, which have few or no collaterals in layer 6; and (5) afferents to the upper half of layer 4C alpha, which have arborizing collaterals in layer 6B. Of the nine axons that were recorded intracellularly, those with projections to layer 4C beta (two axons) and to layer 1 (one axon) had color-selective properties, whereas those (six axons) which arborized in 4C alpha all had transient, broad band and highly contrast-sensitive receptive fields. These properties are consistent with derivations from somata in the parvocellular and magnocellular divisions of the LGN, respectively. Afferents to 4C alpha were found to cover approximately 6 times as much surface area as afferents to 4C beta. The preterminal trunks of all axons were found to follow tortuous paths through the neuropil--paths that may derive from axon segregation during development. The wide ranging, patchy distributions of single afferents in 4C alpha suggest that individual 4C alpha axons supply more than one ocular dominance stripe. In one case where the terminal arborization of a 4C alpha axon was mapped against the transneuronally determined pattern of ocular dominance, three separate patches of terminal boutons were indeed found to coincide with the bands of one eye.

Afferent Pathways↗
PubMed1995

Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels.

We examined the role of extracellular calcium entry, the possible involvement of axonal calcium channels, and the potential protective effect of calcium channel and calpain antagonists in axotomy-induced axonal degeneration using murine dorsal root ganglia in cell culture. We found that calcium entry is both necessary and sufficient to induce axonal degeneration after axotomy, and may be inhibited by cobalt, manganese, dihydropyridines, and bepridil. Tetrodotoxin and omega-conotoxin are ineffective in preventing axonal degeneration. The activation of calpains also appears to be necessary and sufficient for axonal degeneration to proceed, and can be blocked with membrane-permeant leupeptin analogs and the oxirane aloxistatin. Although other calcium-activated events may occur, it appears that inhibition of calpain is sufficient to preserve the axon at the light microscope level, and to prevent axonal cytoskeleton degradation as detected by immunofluorescent staining. Our results suggest that axonal degeneration after axotomy involves the following sequence of events: (1) a lag-period after axotomy prior to the onset of axonal degeneration, (2) entry of calcium into the axon through an intact axolemma via a calcium-specific ion transport mechanism, (3) activation of calcium-dependent effector molecules such as calpains, (4) degradation of the axonal cytoskeleton. The details of the second step require further elucidation, and are of particular interest because this step is a potential target for therapies directed towards peripheral neuropathies.

Animals↗
PubMed1994

The role of oligodendrocytes and myelin on axon maturation in the developing rat retinofugal pathway.

In neonatal mammals, newly grown optic axons are uniformly small in diameter. In the adult, in contrast, axons within the optic nerve can be classified into distinct groups according to their diameter. Because axon diameters are also related to the thickness of the myelin sheath, which in turn determines the velocity of action potential propagation, the question of what determines the axon diameter is of critical importance. In a project aimed at determining the influence of the ensheathing cell on axon maturation, oligodendrocyte development was prevented by eliminating their precursors by unilateral x-irradiation at birth. Axon diameters in both the normal and the myelin-free optic nerves were then measured at varying stages of development. The results demonstrate that axon diameter growth remained substantially reduced in the absence of oligodendrocytes. Interestingly, by x-irradiating the optic nerve and tract on one side of the brain, fibers crossing the chiasm became larger as they went from an unmyelinated nerve to a myelinated tract; fibers on the nonirradiated side became smaller as they went from a myelinated nerve and crossed into the nonmyelinated tract. These results clearly point to a local regulation of axon diameter by oligodendrocytes. Moreover, ganglion cells measured 9 d after the initiation of myelination (postnatal day 6, P6) were of similar size within normal retinas and retinas whose axons were x-irradiated, suggesting that ganglion cell growth occurs in spite of the lack of myelin and axon diameter maturation. Finally, we showed, through both section staining with antibodies to myelin basic protein (MBP) and Northern blot analysis using a probe to MBP, that the x-irradiated nerve began a delayed myelination period (in a gradient from chiasm to eye) at P15 and reached an almost normal myelin pattern at P28. Axons from these nerves grew to seemingly normal diameter concomitant with this delayed myelination.

Aging↗