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PubMed1984

Regeneration of long spinal axons in the rat.

To investigate regeneration of long spinal axons, the right lateral column of the rat spinal cord was cut at high cervical, low cervical, midthoracic or lumbar level, and one end of an autologous sciatic nerve segment was grafted to the spinal cord at the site of incision. Three to six months after operation, the origin of axons in the grafts was traced retrogradely with horseradish peroxidase injected into the grafts and, in some cases, anterogradely with radioautography of tritiated amino acids injected into the brainstem. Axons from each of the major lateral spinal tracts arising in the brainstem as well as axons ascending from the lower spinal cord succeeded in growing into low cervical grafts. However, long descending axons rarely regenerated after midthoracic or lumbar injury; axons ascending from lumbar segments of the spinal cord usually failed to enter high cervical grafts. Differences in axonal regrowth at the four segmental levels were not simply attributable to dwindling of axonal number in fibre tracts. Axonal regeneration from Clarke's column or the red nucleus was observed only with lesions causing atrophy of many neurons. There was no obvious example of a fibre tract in the lateral spinal columns from which axons failed to regenerate nor from which axons regenerated exceptionally well. Under the conditions of these experiments, the distance from cell body to injury appeared to be an important determinant of axonal regeneration.

Animals↗
PubMed2001

Sensitivity of sensory axons to lidocaine nerve block in rats.

The aim of the present study was to test the sensitivity of different classes of sensory axons to lidocaine 2 and 4% nerve block. The basic approach was to examine changes in compound action potential (CAP) of A and C axons of the rat sural nerve induced by 2 or 4% lidocaine nerve block in vitro. CAP in control sural nerves (n = 6 for each experimental group) before nerve block was induced, consisted of the early component (A axons: 0.3 +/- 0.02 ms) and the late component (C axons: 12.2 +/- 1.14 ms) with peak voltage amplitudes 4.4 +/- 1.4 mV and 0.04 +/- 0.02 mV, respectively. Lidocaine 2% nerve block completely abolished the amplitude of CAP of C axons and depressed the amplitude of CAP of A axons to about 20 % of control level. Doubled concentration of lidocaine significantly decreased time taken to develop maximal depression of CAP and significantly increased excitation threshold of sensory A axons, but not of sensory C axons. However, 4% lidocaine did not affect the maximal depression of CAP of sensory A axons. These results support the view, that C axons are more sensitive to lidocaine nerve block than A axons. In addition, our results suggest a population of sensory A axons which is non-sensitive to 2% and 4% lidocaine.

Action Potentials↗
PubMed2005

Patched regulation of axon guidance is by specifying neural identity in the Drosophila nerve cord.

Within an axon bundle, one or two are pioneering axons and the rest are follower axons. Pioneering axons are projected first and the follower axons are projected later but follow a pioneering axon(s) pathway. It is not clear whether the pioneering axons have a guidance role for follower axons. In this paper, we have investigated the role of Patched (Ptc) in regulating the guidance of medial tract, one of the longitudinal tracts in the nerve cord. In patched mutants the medial longitudinal tract fails to fasciculate on its own side along the nerve cord, instead it abnormally crosses the midline and fasciculates with the contralateral tract. Interestingly, the medial tracts cross the midline ignoring the axon-repellant Slit on the midline and Roundabout on growth cones. The medial tract is pioneered by neurons pCC and vMP2. Our results show that guidance defects of this tract are due to loss and mis-specification of vMP2, which results in the projection from pCC to either stall or project outward near the location of vMP2. Thus, both pioneering neurons are necessary for the proper guidance of pioneering and follower axons. We also show that the loss of Ptc activity in the neuroectoderm prior to the formation of S1 and S2 neuroblasts causes the majority of axon guidance defects. These results provide insight into how mis-specification and loss of neurons can non-autonomously contribute to defects in axon pathfinding.

Animals↗
PubMed1980

Synapse formation after injury in the adult rat brain: preferential reinnervation of denervated fimbrial sites by axons of the contralateral fimbria.

The dorsolateral quadrant of the lateral septal nucleus receives projections from both the ipsilateral and the contralateral fimbria. In the adult rat the effect of fimbrial lesions on synapse formation has been studied by a quantitative electron microscopic analysis of the various types of synapses present, using electron-dense degeneration to identify fimbrial fibre terminals. In this area, the fimbrial axons from both sides together account for about 30% of the total number of synapses and they terminate mainly on dendritic spines. The ipsilateral fimbria forms twice as many synapses as the contralateral fimbria. When one fimbria is cut and time left for the degeneration to be removed, the numbers of synapses are restored to normal levels and the remaining fimbria acquires, on both sides of the septum, a number of synapses equal to the sum of the two individual fimbria, This suggests that the axons of the surviving fimbria have completely reinnervated the denervated postsynaptic sites formerly occupied by the cut fimbria of the other side, effectively excluding non-fimbrial axon terminals, even though the latter constitute the majority (70%) of the synaptic terminals in the region. When both fimbria are cut the numbers of synapses are once again restored to normal levels. However, since there are now no fimbrial axons left, the denervated fimbrial postsynaptic sites must this time have been reinnervated by non-fimbrial axons. Reinnervation by non-fimbrial axons is numerically equally effective in reclaiming the denervated sites, although when compared to the reinnervation by fimbrial axons, the removal of degenerating terminals is somewhat slower, and among the reinnervating terminals there is a much higher incidence of axon terminals making more than one synaptic contact in the plane of section. Thus, fimbrial axons, when present, have the ability to exclude the reinnervation of denervated fimbrial sites by non-fimbrial axons, despite the fact that the latter are both more numerous and also clearly capable of reinnervating those sites when no fimbrial axons are present. Two possible mechanisms are discussed: a spatial preference based on the geometrical arrangements in the neuropil, and a temporal preference based on the relative rates of response of the fimbrial vs the non-fimbrial axons.

Animals↗
PubMed1982

Association of spermine and 4S RNA during axonal transport in regenerating optic nerves of goldfish.

Experiments were designed to determine whether polyamines are bound to 4S RNA and then transported axonally along regenerating optic axons of goldfish. In one set of experiments, inhibition of retinal RNA synthesis by intraocular injections of 10 microgram of cordycepin, blocked the axonal transport of both [3H]RNA and [14C]spermidine by about 65%, 6 and 14 days after injection. Intraocular injections of vinblastine, (0.1, 0.5 or 1.0 microgram) an agent which interrupts axonal transport of proteins, had no effect on retinal RNA synthesis nor on the amount of [14C]spermidine incorporated into the TCA-insoluble fraction of retinal extracts. However, the axonal transport of both [3H]RNA and [14C]polyamines was affected in a dose-dependent fashion; the inhibition of both was approximately 80% at the higher dose. Further evidence for an association between axonally transported 4S RNA and polyamines came from experiments in which regenerating optic axons were cut and allowed to degenerate 6 days after injection of [3H]spermidine into the eye. The loss of optic axons from the tectum 7 days after cutting the nerve resulted in an 86% loss of TCA insoluble polyamines, indicating a largely intra-axonal locus. A similar loss of 4S RNA was found in identical experiments following injections of [3H]uridine into the eye. Finally, experiments were performed in which [3H]spermidine was injected into both eyes of 12 fish whose optic nerves had been regenerating for 18 days. Six days later, fish were sacrificed and RNA was extracted from tectal homogenates by hot phenol and ethanol precipitation. The major stable RNA species were separated by SDS-polyacrylamide disc gel electrophoresis and radioactivity was determined by extraction of 2.0 mm gel slices. Results showed co-migration of 3H with 4S RNA optical density peaks, and not with 28S and 18S ribosomal RNA peaks, suggesting that some polyamine-associated radioactivity is bound to axonally transported 4S RNA. When the nature of that radioactivity was determined on an amino acid analyzer, it was found to be present primarily as spermine and not as the injected compound spermidine. The data are consistent with the hypothesis that some spermine is bound to 4S RNA and then axonally transported along regenerating axons of the goldfish optic nerve.

Animals↗
PubMed1986

Morphology of freeze-substituted myelinated axon in mouse peripheral nerves.

In order to clarify the in situ shape of axons, the entire shape of freeze-substituted axons (FS axons) was compared with that of chemically-fixed axons (CF axons) using the serial semi-thin section method coupled with rapid freezing technique. Mouse saphenous nerves were rapidly frozen by being contacted against a pure copper block cooled to 4 K by liquid helium. At the internode, the FS axons showed a cylindrical outline while the CF axons showed a polygonal contour. At regions near the node of Ranvier, both FS and CF axons showed a cog-wheel contour, and at the node they became circular and highly attenuated. These findings indicated that the axons, at the internode, were artifactually distorted during chemical fixation and that the in situ shape of myelinated axons was characterized by the cylindrical internodal segment, the distorted juxtaparanodal segment and the attenuated nodal segment. The physiological meanings of the entire shape of axons were discussed with special reference to the molecular mechanism of slow axonal transport and membrane excitation.

Animals↗
PubMed1988

Cation-binding sites in trigeminal ganglia and maxillary nerve: unusual reactivity of perikarya, stem axons and satellite cells.

We have used the cupric/ferrocyanide reaction to study cation-binding in trigeminal ganglia and maxillary nerve of adult rats. Unmyelinated axons did not react, whereas myelinated axons were stained at nodal, paranodal or cleft sites. At 'nodal' sites, metallic deposits were found in the axoplasm, along the axolemma, and at the extracellular interfaces of the paranodal myelin. At 'paranodal' sites, particles were concentrated in the paranodal axoplasm and in the intracellular spaces of the myelin loops. Most maxillary axons examined at successive sites had all nodal or all paranodal staining, but 13 of 51 had a mixture. In trigeminal ganglia there was no staining of perineurial sheath, endoneurial cells or mast cells. Satellite cells and their basal laminae were prominently stained, with those around small neurons more reactive than those of large neurons. Patches of neuronal membrane on cell bodies were stained, more often for small than large neurons. The axon hillock and proximal stem axon were not stained in some cases, but approximately half the neurons had staining of perikaryal cytoplasm at the axon hillock or a dense asymmetric band in the proximal stem axon. Strong intraaxonal staining was found at the junction between unmyelinated proximal and myelinated distal stem axon. In distal stem axons, staining was found at the first myelin segment and at each successively thicker myelin segment; staining was mostly weak and paranodal, with intensity proportional to myelin thickness. The T-junction between stem and main myelinated axon had nodal or paranodal patterns; unmyelinated T-junctions were not stained. The varied cation-binding patterns in trigeminal ganglia show unusual properties of satellite cells and important differences between stem and main axons. The results that the cell membrane of axon hillock and proximal stem regions of many sensory large and small neurons may have numerous sodium channels and could affect signal propagation.

Animals↗
PubMed1991

Distribution of sodium channels in chronically demyelinated spinal cord axons: immuno-ultrastructural localization and electrophysiological observations.

The immuno-ultrastructural localization of voltage-sensitive sodium channels was demonstrated within a central demyelinating lesion induced in the rat spinal cord by ethidium bromide/irradiation using polyclonal antibody 7493. Antibody 7493 has previously been shown to immunostain intensely axon membrane at nodes of Ranvier, and also perinodal astrocyte processes. At 25-35 days post injection/irradiation, the central portion of the demyelinating lesion is populated with chronically demyelinated axons and there is an absence of glial processes. Sodium channel immunoreactivity was not observed on the chronically demyelinated axolemma within this central portion of the lesion. Within the peripheral portion of the lesion demyelinated axons were occasionally abutted by astrocyte and Schwann cell processes. At these focal sites of apposition, the axon membrane displayed intense sodium channel immunoreactivity, while the abutting astrocyte and Schwann cell processes did not exhibit immunostaining. Also in the periphery of the lesion, some axons become ensheathed and myelinated by oligodendrocytes and Schwann cells. The axon membrane of circumferentially ensheathed axons displayed antibody 7493 immunostaining, and this immunoreactivity persisted on the axolemma until the ensheathing cytoplasmic processes compacted into myelin. Internodal axon membrane beneath the myelin sheath did not display sodium channel immunoreactivity, though (putative) developing nodal axon membrane adjacent to terminal paranodal loops exhibited robust sodium channel staining. Electrophysiological recordings within the ethidium bromide/irradiation lesion demonstrated that at least some axons conducted action potentials within the lesion, while others exhibited conduction block. These results indicate that there is a reorganization of sodium channels within the axon membrane of chronically demyelinated central axons.

4-Aminopyridine↗
PubMed1993

Long axon growth from embryonic neurons transplanted into myelinated tracts of the adult rat spinal cord.

Suspensions of embryonic mouse hippocampal neurons were micro-transplanted into the high cervical region of the corticospinal tracts and the ascending dorsal columns of immunosuppressed adult rat hosts. The mouse specific marker, M6, showed that the transplanted neurons grew long, straight, and uniform axons which passed both rostrally and caudally in a narrow beam within the tract occupied by the transplant. The donor axons did not fasciculate with each other, but were intermingled singly with the host myelinated axons, parallel to them and to the host interfascicular glial rows. The donor axons extended at about 0.5 mm per day for the first 6-10 days, after which they slowed down, gradually reaching a maximum distance of around 8 mm from the grafts by 6-7 weeks. Beyond this time M6 ceased to be an effective marker. The presence of the donor axonal projections was confirmed by retrograde cellular labelling of the donor cells from injections of horseradish peroxidase caudal to the transplants in the same host tract. To test whether the donor embryonic hippocampal axons would be attracted to neuropil containing appropriate postsynaptic sites, embryonic rat hippocampal grafts were placed caudal to the mouse grafts. When placed where they could make direct contact with the projection, the rat grafts became M6 positive, suggesting that they had been innervated by mouse axons. But even when placed directly within the beam of donor projections, the rat grafts did not prevent large numbers of mouse axons from continuing caudally in the host spinal tracts. When the rat grafts were placed to one side of the beam of donor projection, the long projecting mouse axons did not deviate from their course. Thus the long ascending and descending myelinated fibre tracts of the adult spinal cord provide a permissive environment for the rapid growth of axons from embryonic donor neurons from a region not normally projecting to the spinal cord. The route taken by these axons is determined by the internal structure of the host tracts. Donor interfascicular axons are able to pass, without deviation, through or beside tissue containing appropriately matched postsynaptic targets.

Animals↗
PubMed1988

Evidence for dual serotonergic projections to neocortex: axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA).

Previous studies have shown that there are morphologically dissimilar serotonergic (5-HT) axon types in rat cerebral cortex which are differentially sensitive to the neurotoxic effects of certain psychotropic drugs: methylenedioxyamphetamines (MDA and MDMA) and p-chloroamphetamine (PCA) cause degeneration of fine 5-HT axon terminals in cortex, while sparing beaded axons. Moreover, a recent anterograde transport study suggests that fine and beaded 5-HT axons arise from the dorsal raphe (DR) and median raphe (MR) nuclei, respectively. These data led us to propose that the DR projection to neocortex is selectively vulnerable to the neurotoxic effects of PCA, while the MR projection is resistant; this hypothesis was tested in the present study by comparing retrograde axonal transport of the fluorescent tracer Fluoro-Gold in PCA-treated and control rats. Using this method, only axons that survive PCA treatment can take up and transport the injected label back to the cell bodies of origin, thus allowing us to determine which raphe-cortical projections remain intact after PCA. The results show that PCA administration produces a loss of fine 5-HT axon terminals in neocortex and a concomitant reduction in the number of retrogradely labeled neurons in the DR (77% decrease), when compared to controls. In contrast, beaded 5-HT axon terminals are spared and the number of labeled neurons in the MR remains unchanged after PCA. These results demonstrate that DR and MR projections to cortex are differentially vulnerable to PCA: fine axon terminals arise from neurons in the DR and are highly sensitive to the neurotoxic effects, whereas beaded axons from the MR are resistant. We therefore propose that there are two anatomically and functionally separate 5-HT projections to cortex having different (1) nuclei of origin, (2) axon morphology, (3) regional distributions, and (4) pharmacological properties. Since the mood-altering substances MDA, MDMA, and PCA act specifically upon 5-HT axon terminals from the dorsal raphe nucleus, DR neurons may be preferentially involved in the control of affective state.

Amphetamines↗
PubMed1993

Frequency analysis of catecholamine axonal morphology in human brain. I. Effects of postmortem delay interval.

The diverse morphologies of catecholamine axons in the human brain were examined by using tyrosine hydroxylase immunocytochemistry. Human brain tissue was obtained by either rapid autopsy (mean postmortem delay < 1 h) or routine autopsy (mean postmortem delay 5 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus and the calcarine cortex (Brodmann area 17) were processed for tyrosine hydroxylase immunoreactivity. First, a quantitative method was developed to reliably identify differing morphologies of catecholamine axons in human brain tissue. A total of 625 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct morphological categories. These categories were based upon axonal morphologies which were readily distinguished by trained observers, and moreover, further investigations demonstrated that entire tissue sections could be reliably re-sampled at intervals of up to six months. Second, regional variations in axonal distribution and the effects of increasing postmortem delay in tissue processing on the categories of tyrosine hydroxylase immunoreactive axon morphologies were examined. Postmortem delays of up to 6.5 hours were found to decrease the frequency of fine axons with varicosities (axon type 2) and increase thick-caliber straight axons (axon type 5) in all regions examined. The frequency of other morphological axon types did not change as a function of postmortem delay. In summary, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to be reliable and valid. It was furthermore demonstrated that postmortem delays affect selected morphological types of catecholamine axons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2005

Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection.

We have previously shown that a novel synthetic hydrogel channel composed of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (pHEMA-MMA) is biocompatible and supports axonal regeneration after spinal cord injury. Our goal was to improve the number and type of regenerated axons within the spinal cord through the addition of different matrices and growth factors incorporated within the lumen of the channel. After complete spinal cord transection at T8, pHEMA-MMA channels, having an elastic modulus of 263+/-13 kPa were implanted into adult Sprague Dawley rats. The channels were then filled with one of the following matrices: collagen, fibrin, Matrigel, methylcellulose, or smaller pHEMA-MMA tubes placed within a larger pHEMA-MMA channel (called tubes within channels, TWC). We also supplemented selected matrices (collagen and fibrin) with neurotrophic factors, fibroblast growth factor-1 (FGF-1) and neurotrophin-3 (NT-3). After channel implantation, fibrin glue was applied to the cord-channel interface, and a duraplasty was performed with an expanded polytetrafluoroethylene (ePTFE) membrane. Controls included animals that had either complete spinal cord transection and implantation of unfilled pHEMA-MMA channels or complete spinal cord transection. Regeneration was assessed by retrograde axonal tracing with Fluoro-Gold, and immunohistochemistry with NF-200 (for total axon counts) and calcitonin gene related peptide (CGRP, for sensory axon counts) after 8 weeks survival. Fibrin, Matrigel, methylcellulose, collagen with FGF-1, collagen with NT-3, fibrin with FGF-1, and fibrin with NT-3 increased the total axon density within the channel (ANOVA, p<0.05) compared to unfilled channel controls. Only fibrin with FGF-1 decreased the sensory axon density compared to unfilled channel controls (ANOVA, p<0.05). Fibrin promoted the greatest axonal regeneration from reticular neurons, and methylcellulose promoted the greatest regeneration from vestibular and red nucleus neurons. With Matrigel, there was no axonal regeneration from brainstem motor neurons. The addition of FGF-1 increased the axonal regeneration of vestibular neurons, and the addition of NT-3 decreased the total number of axons regenerating from brainstem neurons. The fibrin and TWC showed a consistent improvement in locomotor function at both 7 and 8 weeks. Thus, the present study shows that the presence and type of matrix contained within synthetic hydrogel guidance channels affects the quantity and origin of axons that regenerate after complete spinal cord transection, and can improve functional recovery. Determining the optimum matrices and growth factors for insertion into these guidance channels will improve regeneration of the injured spinal cord.

Animals↗
PubMed2003

Intracerebral injection of AMPA causes axonal damage in vivo.

Brain injury following acute and chronic neurological conditions can involve both neuronal perikaryal and axonal damage, yet considerably less is known about the mechanisms of axonal damage. Oligodendrocytes and myelin are highly vulnerable to AMPA receptor-mediated excitotoxicity. In vitro studies using isolated white matter preparations have shown that AMPA receptor-mediated excitotoxicity results in axonal damage. The effect of AMPA on axons in vivo remains to be determined. We established an in vivo model to determine if axons were vulnerable to AMPA-mediated toxicity, and furthermore, to examine if axonal damage occurred through an AMPA receptor-mediated mechanism. Adult rats received stereotaxic injection of AMPA (2.5 or 25 nmol) or vehicle (PBS) into the external capsule. Axonal damage was detected in the external capsule and cortex in sections immunostained for cytoskeletal components microtubule associated protein-5 (MAP 5), the 200 kDa neurofilament subunit (NF 200) and non-phosphorylated neurofilament-H (SMI 32). Quantification of axonal damage in the external capsule of MAP 5-immunostained sections showed that AMPA caused a significant, dose-dependent increase in axonal damage compared to the vehicle-treated controls. AMPA also induced a dose-dependent increase in myelin and neuronal perikaryal damage. Systemic administration of the AMPA receptor antagonist SPD 502 significantly reduced the amount of AMPA-induced axonal, myelin and neuronal damage. These data suggest that AMPA induces structural damage to the cytoskeleton of axons in vivo, as well as neuronal and myelin damage, and that this occurs through AMPA receptor-mediated mechanisms. AMPA receptor antagonism may have therapeutic potential to salvage both axons and neuronal perikarya in a number of neurological disorders.

Animals↗
PubMed2006

Latent addition in human motor and sensory axons: different site-dependent changes across the carpal tunnel related to persistent Na+ currents.

OBJECTIVE: To compare site-dependent changes across the carpal tunnel in axonal persistent Na+ conductances in motor and sensory axons. Positive sensory symptoms are prominent features in carpal tunnel syndrome, and a persistent Na+ current is a major determinant of axonal excitability. METHODS: The technique of latent addition was used to estimate persistent Na+ currents in median motor and sensory axons at the wrist and palm of 10 normal subjects. Brief hyperpolarizing conditioning current pulses were delivered, and threshold change at the conditioning-test interval of 0.2 ms was measured as an indicator of persistent Na+ currents. RESULTS: Threshold changes at 0.2 ms were greater in sensory than in motor axons at both the wrist and palm. In motor axons, the threshold changes were significantly smaller at the palm (mean, 4.9%) than at the wrist (10.0%). By contrast, the threshold changes were similar at the two sites of sensory axons (12.6 and 13.1%). The passive membrane time constant was similar for motor and sensory axons at the palm and wrist. CONCLUSIONS: Nodal persistent Na+ conductances have substantial site-dependent changes decreasing distally across the carpal tunnel in median motor axons, but not in sensory axons. SIGNIFICANCE: Whereas sensory axons generally have higher excitability than motor axons, the sensory-motor differences become more prominent across, and possibly at the carpal tunnel than the nerve trunk, and it is suggested that this contributes to the predominance of positive sensory symptoms in carpal tunnel syndrome.

Action Potentials↗
PubMed2004

Engulfing action of glial cells is required for programmed axon pruning during Drosophila metamorphosis.

BACKGROUND: Axon pruning is involved in establishment and maintenance of functional neural circuits. During metamorphosis of Drosophila, selective pruning of larval axons is developmentally regulated by ecdysone and caused by local axon degeneration. Previous studies have revealed intrinsic molecular and cellular mechanisms that trigger this pruning process, but how pruning is accomplished remains essentially unknown. RESULTS: Detailed analysis of morphological changes in the axon branches of Drosophila mushroom body (MB) neurons revealed that during early pupal stages, clusters of neighboring varicosities, each of which belongs to different axons, disappear simultaneously shortly before the onset of local axon degeneration. At this stage, bundles of axon branches are infiltrated by the processes of surrounding glia. These processes engulf clusters of varicosities and accumulate intracellular degradative compartments. Selective inhibition of cellular functions, including endocytosis, in glial cells via the temperature-sensitive allele of shibire both suppresses glial infiltration and varicosity elimination and induces a severe delay in axon pruning. Selective inhibition of ecdysone receptors in the MB neurons severely suppressed not only axon pruning but also the infiltration and engulfing action of the surrounding glia. CONCLUSIONS: These findings strongly suggest that glial cells are extrinsically activated by ecdysone-stimulated MB neurons. These glial cells infiltrate the mass of axon branches to eliminate varicosities and break down axon branches actively rather than just scavenging already-degraded debris. We therefore propose that neuron-glia interaction is essential for the precisely coordinated axon-pruning process during Drosophila metamorphosis.

Alleles↗
PubMed2004

Zebrafish topped is required for ventral motor axon guidance.

Zebrafish primary motor axons extend along stereotyped pathways innervating distinct regions of the developing myotome. During development, these axons make stereotyped projections to ventral and dorsal myotome regions. Caudal primary motoneurons, CaPs, pioneer axon outgrowth along ventral myotomes; whereas, middle primary motoneurons, MiPs, extend axons along dorsal myotomes. Although the development and axon outgrowth of these motoneurons has been characterized, cues that determine whether axons will grow dorsally or ventrally have not been identified. The topped mutant was previously isolated in a genetic screen designed to uncover mutations that disrupt primary motor axon guidance. CaP axons in topped mutants fail to enter the ventral myotome at the proper time, stalling at the nascent horizontal myoseptum, which demarcates dorsal from ventral axial muscle. Later developing secondary motor nerves are also delayed in entering the ventral myotome whereas all other axons examined, including dorsally projecting MiP motor axons, are unaffected in topped mutants. Genetic mosaic analysis indicates that Topped function is non-cell autonomous for motoneurons, and when wild-type cells are transplanted into topped mutant embryos, ventromedial fast muscle are the only cell type able to rescue the CaP axon defect. These data suggest that Topped functions in the ventromedial fast muscle and is essential for motor axon outgrowth into the ventral myotome.

Animals↗
PubMed1998

Alteration of the neurofilament sidearm and its relation to neurofilament compaction occurring with traumatic axonal injury.

Traumatic injury evokes two characteristic forms of focal axonal injury, one of which involves focal perturbation of axolemmal permeability associated with rapid compaction of the underlying axonal neurofilament lattice and microtubular loss. In this process, the neurofilament sidearms have been the subject of intense scrutiny in relation to their role in this NF compaction, with the suggestion that the sidearms, thought to maintain interfilament distance, are proteolytically cleaved and degraded at the time of injury. The current communication addresses the fate of the NF sidearms in such injured axons. Adult cats were subjected to moderate/severe fluid percussion brain injury after intrathecal administration of horseradish peroxidase (HRP). This tracer, excluded by the intact axolemma of uninjured axons, was used to recognize injured axons via HRP intra-axonal uptake/flooding with HRP. Animals were perfused and processed for light microscopic and electron microscopic study of both HRP-containing and non-HRP-containing axons from the same field. HRP-containing axons consistently displayed evidence of traumatically-induced (NF) cytoskeletal collapse. Electron micrographs of HRP-containing axons as well as uninjured, non-HRP-containing axons from the same fields were videographically captured, digitized, enlarged and analysed for NF sidearm length and NF density. HRP-containing axons were found to have increased NF density. Surprisingly, this increased NF density occurred despite the retention of the NF sidearms, which now, however, were reduced in height in comparison to the non-HRP-containing uninjured axons. These observations are not consistent with previously published reports suggesting that overt proteolytic degradation of sidearms was responsible for NF compaction. Based on our findings, we suggest that the NF compaction associated with traumatically-induced axolemmal permeability changes may have its genesis in more subtle sidearm modification, perhaps involving a change in phosphorylation state.

Animals↗
PubMed2003

Signals from the cerebellum guide the pathfinding of inferior olivary axons.

During development, inferior olivary axons cross the floor plate and project from the caudal to the rostral hindbrain, whence they grow into the cerebellar plate. We have investigated the axon guidance signals involved in the formation of this projection in vitro. When the cerebellar plate was grafted ectopically along the margin of the hindbrain in organotypic cultures, inferior olivary axons could pathfind to the ectopic cerebellum, establishing a topographically normal projection. Following rostrocaudal reversal of a region of tissue in the axon pathway between the inferior olive and the cerebellum, olivary axons still navigated towards the cerebellum. Moreover, olivary axons could cross a bridging tissue explant (spinal cord) to reach a cerebellar explant. In collagen gel cultures of inferior olive explants, olivary axon outgrowth increased significantly in the presence of cerebellar explants and axons deflected towards the cerebellar tissue. These results show that the cerebellum is a source of diffusible axon guidance signals for olivary axons. We also found that, in organotypic cultures, olivary axons which had crossed the floor plate showed an increased tendency to respond to cerebellar cues. Taken together, these results indicate that the cerebellum is the source of cues that are chemoattractant and growth-promoting for inferior olivary axons; prior exposure to the floor plate increases responsiveness to these cues.

Animals↗