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PubMed2000

Morphometric analysis of the myelin-associated oligodendrocytic basic protein-deficient mouse reveals a possible role for myelin-associated oligodendrocytic basic protein in regulating axonal diameter.

Myelin-associated oligodendrocytic basic protein is a member of the proteins constituting the central nervous system myelin. By morphometric analysis, we demonstrated that axons of myelin-associated oligodendrocytic basic protein-deficient mice had larger diameters and more myelin lamellae as compared to those of wild-type mice at the same age. It is known that the number of myelin lamellae increases linearly with axonal diameter, and that the rate of radial axonal growth is the factor controlling the rate of myelin formation. In line with these observations, we found that the regression line for axonal diameter and the number of myelin lamellae in myelin-associated oligodendrocytic basic protein-deficient mice appeared to be identical to that in wild-type mice, indicating that the increase in the number of myelin lamellae was the result of the increase in axonal diameter. Furthermore, we generated myelin basic protein/myelin-associated oligodendrocytic basic protein-double-deficient mice through mating myelin-associated oligodendrocytic basic protein-deficient mice with shiverer mice, an autosomal recessive mutant characterized by a lack of all isoforms of myelin basic protein. With these knock-out mice, we showed that axons of the double-deficient mice had larger diameters and smaller form factor, an index of the deformation of the fiber contour, in ensheathed fibers than those of shiverer mice, although there was no difference in axonal diameter of unmyelinated fibers between them. Taken together, myelin-associated oligodendrocytic basic protein seemed to play a role in controlling axonal diameter and in keeping axons round.

Animals↗
PubMed2000

Axonal regeneration from CNS neurons in the cerebellum and brainstem of adult rats: correlation with the patterns of expression and distribution of messenger RNAs for L1, CHL1, c-jun and growth-associated protein-43.

Some neurons in the brain and spinal cord will regenerate axons into a living peripheral nerve graft inserted at the site of injury, others will not. We have examined the patterns of expression of four molecules thought to be involved in developmental and regenerative axonal growth, in the cerebellum and brainstem of adult rats, following the implantation into the cerebellum of peripheral nerve grafts. We also determined how the expression patterns observed correlate with the abilities of neurons in these regions to regenerate axons. Three days to 16 weeks after insertion of living tibial nerve autografts, neurons which had regenerated axons into the graft were retrogradely labelled from the distal extremity of the graft with cholera toxin conjugated to horseradish peroxidase, and sections through the cerebellum and brainstem were processed for visualization of transported tracer and/or hybridized with riboprobes to detect messenger RNAs for the cell recognition molecules L1 and CHL1 (close homologue of L1), growth-associated protein-43 and the cellular oncogene c-jun. Retrogradely labelled neurons were present in cerebellar deep nuclei close to the graft and in brainstem nuclei known to project to the cerebellum. Neurons in these same nuclei were found to have up-regulated expression of all four messenger RNAs. Individual retrogradely labelled neurons also expressed high levels of L1, CHL1, c-jun or growth-associated protein-43 messenger RNAs (and vice versa), and every messenger RNA investigated was co-localized with at least one other messenger RNA. Purkinje cells did not regenerate axons into the graft or up-regulate L1, CHL1 or growth-associated protein-43 messenger RNAs, but there was increased expression of c-jun messenger RNA in some Purkinje cells close to the graft. Freeze-killed grafts produced no retrograde labelling of neurons, and resulted in only transient and low levels of up-regulation of the tested molecules, mainly L1 and CHL1. These findings show that cerebellar deep nucleus neurons and precerebellar brainstem neurons, but not Purkinje cells, have a high propensity for axon regeneration, and that axonal regeneration by these neurons is accompanied by increased expression of L1, CHL1, c-jun and growth-associated protein-43. Furthermore, although the patterns of expression of the four molecules investigated are not identical in regenerating neuronal populations, it is probable that all four are up-regulated in all neurons whose axons regenerate into the grafts and that their up-regulation may be required for axon regeneration to occur. Finally, because c-jun up-regulation is seen in Purkinje cells close to the graft, unaccompanied by up-regulation of the other molecules investigated, c-jun up-regulation alone cannot be taken to reliably signify a regenerative response to axotomy.

Animals↗
PubMed2000

Directed axonal growth towards axolotl limb blastemas in vitro.

Limb amputation in urodele amphibia is followed by formation of a blastema, which subsequently develops into a complete limb with normal pattern of innervation. In this study, we investigated the effects of axolotl limb blastemas on axonal growth in gels of collagen and extracellular matrix (matrigel). When peripheral nerves with attached dorsal root ganglia were cultured in collagen gels together with blastemas, axonal outgrowth was markedly increased compared with control preparations. Blastemas contain fibroblast growth factors, and may also contain neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, neurotrophin 3, neurotrophin 4, glial cell line-derived neurotrophic factor and hepatocyte growth factor/scatter factor, since these factors are expressed in developing limbs in other vertebrates. In collagen gels the neurotrophins and glial cell line-derived neurotrophic factor stimulated axonal growth, but outgrowing axons were shorter than in co-cultures with blastemas. The tyrosine kinase inhibitor K252a blocked the stimulatory effects of the neurotrophins on axonal growth but had relatively little effect on axonal growth in co-cultures with blastemas. In experiments in which peripheral nerves, with attached dorsal root ganglia, were cultured in matrigel, axons grew towards blastemas over distances of about 1mm. Directed axonal growth even occurred in these co-cultures after addition of high concentrations of all the above neurotrophic factors, suggesting that blastemas may release a different factor which stimulates axonal growth. The results indicate that during early stages of limb regeneration in amphibia, factor(s) are released which are capable of attracting the growth of peripheral nerves and may play an important role in the development of innervation of regenerated limbs. The identity of the factor(s) remains to be determined.

Ambystoma mexicanum↗
PubMed2001

Dopamine transporter-immunoreactive axons in the mediodorsal thalamic nucleus of the macaque monkey.

The reciprocal connections between the mediodorsal thalamic nucleus and the prefrontal cortex participate in a circuit that is essential to a number of higher cognitive processes. Projections from the dopamine-containing cells of the ventral mesencephalon to the prefrontal cortex are also critical for these cognitive abilities. It is unclear, however, whether dopamine axons innervate the mediodorsal thalamic nucleus in primates. In order to address this question, we examined the distribution of dopamine transporter-immunoreactive axons in the mediodorsal thalamic nucleus of macaque monkeys. Labeled axons were distributed quite heterogeneously in this nucleus, and did not strictly follow cytoarchitectonic subdivision boundaries. The ventral and lateral portions of the mediodorsal thalamic nucleus, which include parts of the parvicellular and multiform subdivisions, had the highest density of dopamine transporter-immunoreactive axons. In contrast, the dorsomedial portion, which included primarily the magnocellular subdivision, had the lowest density of labeled axons. In both lightly and densely innervated portions of the nucleus, small, dense clusters of dopamine transporter-immunoreactive axons were present. Axons immunoreactive for tyrosine hydroxylase were distributed in a pattern very similar to that of dopamine transporter-labeled axons. In contrast, noradrenergic axons, as revealed by dopamine beta-hydroxylase immunoreactivity, were present in higher density and were more evenly distributed throughout the mediodorsal thalamic nucleus. This dopamine innervation of the mediodorsal thalamic nucleus reveals another possible anatomical substrate through which dopamine may influence the cognitive functions mediated by thalamo-prefrontal circuitry.

Animals↗
PubMed1998

Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

In previous studies m2 muscarinic acetylcholine receptor-immunoreactive interneurons and various types of m2-positive axon terminals have been described in the hippocampal formation. The aim of the present study was to identify the types of interneurons expressing m2 receptor and to examine whether the somadendritic and axonal m2 immunostaining labels the same or distinct cell populations. In the CA1 subfield, neurons immunoreactive for m2 have horizontal dendrites, they are located at the stratum oriens/alveus border and have an axon that project to the dendritic region of pyramidal cells. In the CA3 subfield and the hilus, m2-positive neurons are multipolar and are scattered in all layers except stratum lacunosum-moleculare. In stratum pyramidale of the CA1 and CA3 regions, striking axon terminal staining for m2 was observed, surrounding the somata and axon initial segments of pyramidal cells in a basket-like manner. The co-localization of m2 with neurochemical markers and GABA was studied using the "mirror" technique and fluorescent double-immunostaining at the light microscopic level and with double-labelling using colloidal gold-conjugated antisera and immunoperoxidase reaction (diaminobenzidine) at the electron microscopic level. GABA was shown to be present in the somata of most m2-immunoreactive interneurons, as well as in the majority of m2-positive terminals in all layers. The calcium-binding protein parvalbumin was absent from practically all m2-immunoreactive cell bodies and dendrites. In contrast, many of the terminals synapsing on pyramidal cell somata and axon initial segments co-localized parvalbumin and m2, suggesting a differential distribution of m2 receptor immunoreactivity on the axonal and somadendritic membrane of parvalbumin-containing basket and axo-axonic cells. The co-existence of m2 receptors with the calcium-binding protein calbindin and the neuropeptides cholecystokinin and vasoactive intestinal polypeptide was rare throughout the hippocampal formation. Only calretinin and somatostatin showed an appreciable degree of co-localization with m2 (20% and 15%, respectively). Using retrograde tracing, some of the m2-positive cells in stratum oriens were shown to project to the medial septum, accouting for 38% of all projection neurons. The present results demonstrate that there is a differential distribution of m2 receptor immunoreactivity on the axonal vs the somadendritic membranes of distinct interneuron types and suggest that acetylcholine via m2 receptors may reduce GABA release presynaptically from the terminals of perisomatic inhibitory cells, while it may act to increase the activity of another class of interneuron, which innervates the dendritic region of pyramidal cells.

Animals↗
PubMed1999

Ribosomes and polyribosomes are present in the squid giant axon: an immunocytochemical study.

Ribosomes and polyribosomes were detected by immuno-electron microscopy in the giant axon and small axons of the squid using a polyclonal antibody against rat brain ribosomes. The ribosomal fraction used as antigen was purified by ultracentrifugation on a sucrose density gradient and shown to contain ribosomal RNAs and native ribosomes. The polyclonal antibody raised in rabbits reacted with at least ten proteins on immunoblots of purified rat brain ribosomes as well as with a set of multiple ribosomal proteins prepared from the squid giant fiber lobe. Immunoreactions were performed on cryostat sections of the stellate nerve cut at a distance of more than 3 cm from the stellate ganglion, using pre-embedding techniques. Ribosomes and polyribosomes were identified within the giant axon and small axons using electron microscopic methods, following binding of peroxidase-conjugated anti-rabbit IgG secondary antibody. Polysomes were more frequently localized in peripheral axoplasm, including the cortical layer of the giant axon, and were generally associated with unidentified cytoskeletal filaments or with dense matrix material. The immunochemical demonstration of ribosomes and polyribosomes in the giant axon and small axons of the squid confirms similar observations in the squid and the goldfish obtained with the method of electron spectroscopic imaging, and strongly supports the view that a local system of protein synthesis is present in axons. The immunochemical method here described offers an alternative tool for the selective identification of ribosomes, and is likely to prove of value in the analyses of other axonal systems.

Animals↗
PubMed1992

The relative time course of axonal loss from the optic nerve of the developing guinea pig is consistent with that of other mammals.

The relative timing of a number of events during the development of the visual system has recently been suggested to be consistent across a number of mammalian species (Dreher & Robinson, 1988). Some conflicting reports, however, had suggested that the precocial guinea pig might represent an exception to the generalized scheme. A quantitative study was thus carried out on the development of the optic nerve and retina of the guinea pig. Consistent with the prediction of a stable relative time course of mammalian visual development, axons and growth cones were found in the optic stalk from the 24th postconceptional day (40% of the period from conception to eye opening--the cecal period), the peak number of axons was observed on the 32nd postconceptional day (56% of the cecal period), and the phase of rapid axonal loss extended to the 39th and 42nd postconceptional days (68-74% of the cecal period). The number of axons in the adult optic nerve (117,000) represented about 37% of the peak number of axons. Additional observations indicated that during development of the optic nerve the mean axonal diameter increased approximately threefold from 0.31 microns to 1.06 microns. As in other mammals studied so far, myelination was first noted after the period of rapid axonal loss and continued until in the adult 97% of axons were found to be myelinated. In the retina, the presence of pyknotic profiles in the ganglion cell layers extends throughout the periods of loss of the optic nerve axons. Finally, the presence of pyknotic profiles in the amacrine sublayer suggest that in the guinea pig, as in other mammalian species, there is a loss of displaced amacrine cells as well as ganglion cells from the ganglion cell layer.

Animals↗
PubMed1989

Bistratified distribution of terminal arbors of individual axons projecting from area V1 to middle temporal area (MT) in the macaque monkey.

In the present study, the anterograde tracer Phaseolus vulgaris-leucoagglutinin was injected into area V1 in order to demonstrate the detailed morphology of individual axons terminating in prestriate area MT. On the basis of 24 axon reconstructions, several representative (but not necessarily comprehensive) characteristics have been identified: (1) Most axons arborize in a patchy manner over a widespread territory, frequently greater than 1.0 mm and often up to 1.5 x 1.8 mm (dimensions uncorrected for shrinkage). (2) Terminal arbors are distributed to layers 3, 4, and 6. Those in layer 6 need not be in register with those in the upper layers. (3) Number and size of terminal arbors are variable. One axon may have 1-4 arbors in the middle layers; typically at least one of these will have a diameter of 200-250 microns, while the others may be less developed. There are from 1-3 arbors in layer 6, usually 50 microns (but sometimes up to 100 microns) in diameter. (4) Terminal boutons are of mixed morphology, but usually beaded and large (up to 3.0 microns). (5) In the white matter, many axons travel in the external sagittal stratum but some are part of the U-fiber system. Axons commonly branch, sometimes at depths up to 0.75-1.0 mm, below the gray matter of MT. In summary, these axons are not stereotyped, but rather vary in the number and size of their terminal arbors, as well as in their branching and overall geometry. Connections from area V1 to MT have been associated with the magnocellular-dominated "processing channel." As widespread arborizations and bistratified terminations are common to both striate axons in MT and to geniculocortical axons in layer 4C alpha of primary visual cortex, these features might be correlated with magnocellular-specific processing requirements.

Animals↗
PubMedDate not supplied

Organization of retinal ganglion cell axons in the optic fiber layer and nerve of fetal ferrets.

Previous authors have hypothesized that retinotopic projections may be influenced by 'preordering' of the axons as they grow towards their targets. In some nonmammalian species, axons are reorganized at or near the optic nerve head to establish a retinotopic order. Data are ambiguous concerning the retinotopy of the mammalian retinal nerve fiber layer and whether fibers become reorganized at the optic nerve head. We have examined this question in fetal and newborn ferrets (Mustela putorius furo) by comparing the arrangement of axons in the retinal nerve fiber layer with that in the optic nerve. Dil or DiA crystals were implanted into fixed tissue in the innermost layers of the retinal periphery, or at a location midway between the periphery and the optic nerve head. Fluorescence labelling was examined in 100-200 microns Vibratome sections, or the eyecup and nerve were photooxidized and 1-2 microns longitudinal or transverse sections were examined. Regardless of fetal age, eccentricity or quadrant of the implant site, a segregation of labelled peripheral axons from unlabelled central ones was not detected within the nerve fiber layer. Axons coursed into the nerve head along the margin of their retinal quadrant of origin, often entering the optic nerve as a radial wedge, thus preserving a rough map of retinal circumference. However, peripheral axons were in no way restricted to the peripheral (nor central) portions of the nerve head or nerve, indicating that the optic axons do not establish a map of retinal eccentricity. Our results demonstrate that (1) the nerve fiber layer is retinotopic only with respect to circumferential position and (2) optic axons are not actively reorganized to establish a retinotopic ordering at the nerve head. The present results suggest that any degree of order present within the optic nerve is a passive consequence of combining the fascicles of the retinal nerve fiber layer; optic axons are not instructed to establish, nor constrained to maintain, a retinotopic order within the optic nerve.

Animals↗
PubMedDate not supplied

Morphology of human retinal ganglion cells with intraretinal axon collaterals.

Ganglion cells with intraretinal axon collaterals have been described in monkey (Usai et al., 1991), cat (Dacey, 1985), and turtle (Gardiner & Dacey, 1988) retina. Using intracellular injection of horseradish peroxidase and Neurobiotin in in vitro whole-mount preparations of human retina, we filled over 1000 ganglion cells, 19 of which had intraretinal axon collaterals and wide-field, spiny dendritic trees stratifying in the inner half of the inner plexiform layer. The axons were smooth and thin (approximately 2 microm) and gave off thin (<1 microm), bouton-studded terminal collaterals that extended vertically to terminate in the outer half of the inner plexiform layer. Terminal collaterals were typically 3-300 microm in length, though sometimes as long as 700 microm, and were present in clusters, or as single branched or unbranched varicose processes with round or somewhat flattened lobular terminal boutons 1-2 microm in diameter. Some cells had a single axon whereas other cells had a primary axon that gave rise to 2-4 axon branches. Axons were located either in the optic fiber layer or just beneath it in the ganglion cell layer, or near the border of the ganglion cell layer and the inner plexiform layer. This study shows that in the human retina, intraretinal axon collaterals are associated with a morphologically distinct ganglion cell type. The synaptic connections and functional role of these cells are not yet known. Since distinct ganglion cell types with intraretinal axon collaterals have also been found in monkey, cat, and turtle, this cell type may be common to all vertebrate retinas.

Axons↗
PubMed1999

Optic nerve regeneration after intravitreal peripheral nerve implants: trajectories of axons regrowing through the optic chiasm into the optic tracts.

We have studied axon regeneration through the optic chiasm of adult rats 30 days after prechiasmatic intracranial optic nerve crush and serial intravitreal sciatic nerve grafting on day 0 and 14 post-lesion. The experiments comprised three groups of treated rats and three groups of controls. All treated animals received intravitreal grafts either into the left eye after both left sided (unilateral) and bilateral optic nerve transection, or into both eyes after bilateral optic nerve transection. Control eyes were all sham grafted on day 0 and 14 post-lesion, and the optic nerves either unlesioned, or crushed unilaterally or bilaterally. No regeneration through the chiasm was seen in any of the lesioned control optic nerves. In all experimental groups, large numbers of axons regenerated across the optic nerve lesions ipsilateral to the grafted eyes, traversed the short distal segment of the optic nerve and invaded the chiasm without deflection. Regeneration was correlated with the absence of the mesodermal components in the scar. In all cases, axon regrowth through the chiasm appeared to establish a major crossed and a minor uncrossed projection into both optic tracts, with some aberrant growth into the contralateral optic nerve. Axons preferentially regenerated within the degenerating trajectories from their own eye, through fragmented myelin and axonal debris, and reactive astrocytes, oligodendrocytes, microglia and macrophages. In bilaterally lesioned animals, no regeneration was detected in the optic nerve of the unimplanted eye. Although astrocytes became reactive and their processes proliferated, the architecture of their intrafascicular processes was little perturbed after optic nerve transection within either the distal optic nerve segment or the chiasm. The re-establishment of a comparatively normal pattern of passage through the chiasm by regenerating axons in the adult might therefore be organised by this relatively immutable scaffold of astrocyte processes. Binocular interactions between regenerating axons from both nerves (after bilateral optic nerve transection and intravitreal grafting), and between regenerating axons and the intact transchiasmatic projections from the unlesioned eye (after unilateral optic nerve lesions and after ipsilateral grafting) may not be important in establishing the divergent trajectories, since regenerating axons behave similarly in the presence and absence of an intact projection from the other eye.

Age Factors↗
PubMed1997

Basic fibroblast growth factor promotes extension of regenerating axons of peripheral nerve. In vivo experiments using a Schwann cell basal lamina tube model.

Schwann cell basal lamina tubes serve as attractive conduits for regeneration of peripheral nerve axons. In the present study, by using basal lamina tubes prepared by in situ freeze-treatment of rat saphenous nerve, the effects of exogenously applied basic fibroblast growth factor (bFGF) on peripheral nerve regeneration was examined 2 and 5 days after bFGF administration. Regenerating axons were observed by light and electron microscopy using PGP9.5-immunohistochemistry for specific staining of axons. In addition, the localizations of bFGF and its receptor (FGF receptor-1) were examined by immunohistochemistry using anti-bFGF antibody and anti-FGF receptor-1 antibody, respectively. Regenerating axons extended further in the bFGF-administered segment than in the bFGF-untreated control segment. Electron microscopy showed that regenerating axons grew out unaccompanied by Schwann cells. Findings concerning angiogenesis and Schwann cell migration were very similar between the bFGF treated and control nerve segment. bFGF-immunoreactivity was not detected in the control nerve segment. In contrast, bFGF-immunoreactivity was detected on the basal lamina tubes as well as on the plasmalemma of regenerating axons facing the basal lamina in the bFGF treated nerve segment up to 5 days after administration, suggesting that exogenous bFGF can be retained in the basal lamina for several days after administration. FGF receptor was detected on the plasma membrane of regenerating axons where they abutted the basal lamina. These results indicate that bFGF could promote the extension of early regenerating axons by directly influencing the axons, but not via Schwann cells or angiogenesis.

Animals↗
PubMed1997

Axon-glial relationships in early CNS-PNS transitional zone development: an ultrastructural study.

The CNS-PNS transitional zone of rat cervical ventral rootlets develops in two stages: first, axon segregation, then transitional node formation. This ultrastructural study examines the former. Material was prepared by standard methods. Shortly after they grow out from the neural tube, ventral motoneuron axon bundles are extensively segregated by a matrix of fine processes forming a barrier across the rootlet, just distal to the cord surface. These processes arise from cell clusters on the rootlet surface. This barrier is prominent until the period around birth, when it is replaced by a second in which the axons are completely segregated from one another. The perikarya and processes forming this barrier resemble those of the first, but lie at or just below the cord surface. Thus, beginning at the earliest stage, a barrier crosses the axon bundle and segregates its axons before axon segregation is advanced either in the PNS or (especially) in the CNS. This may prevent central Schwann cell migration. Evidence is presented suggesting that the second barrier may arise through a relative proximal relocation of the first, as the cord grows radially. Near the cord surface, a complete, funnel-shaped sleeve of glial processes surrounds the axon bundle. This is continuous at the cord surface with the glia limitans. It constitutes an integral part of the transitional zone apparatus. It is also continuous centrally with the sheath which enfolds the bundle of ventral motoneuron axons as they run between the ventral horn and the transitional zone. Axon segregation at the cord surface, and therefore the formation of the definitive astrocytic CNS-PNS barrier occur relatively (and perhaps surprisingly) late at the cord surface. The definitive sharp discontinuity of central and peripheral tissue types characteristic of the transitional zone is established only after birth.

Aging↗
PubMed2000

Calcitonin gene-related peptide, substance P and protein gene product 9.5 immunoreactive axonal fibers in the rat footpad skin following partial sciatic nerve injuries.

Chronic constriction injury (CCI) and partial ligation (PSNL) of the sciatic nerve induce a similar neuropathic pain syndrome in rats. We examined calcitonin gene-related peptide (CGRP), substance P (SP) and protein gene product (PGP) 9.5 immunoreactive (IR) axons in the footpad skin after the two types of injury. Four and 14 days after CCI, CGRP- and SP-IR axons in the ipsilateral footpad skin disappeared in most rats, but in one third, sparse CGRP- and SP-IR fibers remained. PGP-IR axons dramatically decreased, but some thick fiber fascicles appeared. At the ultrastructural level, these PGP-IR thick fiber fascicles were characterized as unmyelinated axons surrounded by non-IR Schwann cells. Some of these axons were swollen and irregular in shape. In contrast, 4 days after PSNL, CGRP-, SP-, and PGP-IR axons in the ipsilateral footpad skin were present, though significantly reduced in density, in all rats, and by 14 days all IR fiber densities in the footpad skin partially recovered. The loss of CGRP and SP axons in the footpad skin of the CCI model suggests that sensory nerves containing neuropeptides are not essential in transducing stimuli applied to the footpad skin into neuropathic pain, but the abnormal PGP-IR unmyelinated axons in thick fiber fascicles might play a role. The partial loss and rapid recovery of IR axons in the footpad skin after PSNL shows that the two injury models, causing similar behaviors, are associated with very different patterns of cutaneous innervation at the time when the pain syndrome is well developed.

Animals↗
PubMed2000

Schwann cells in the regenerating fish optic nerve: evidence that CNS axons, not the glia, determine when myelin formation begins.

Fish optic nerve fibres quickly regenerate after injury, but the onset of remyelination is delayed until they reach the brain. This recapitulates the timetable of CNS myelinogenesis during development in vertebrate animals generally, and we have used the regenerating fish optic nerve to obtain evidence that it is the axons, not the myelinating glial cells, that determine when myelin formation begins. In fish, the site of an optic nerve injury becomes remyelinated by ectopic Schwann cells of unknown origin. We allowed these cells to become established and then used them as reporters to indicate the time course of pro-myelin signalling during a further round of axonal outgrowth following a second upstream lesion. Unlike in the mammalian PNS, the ectopic Schwann cells failed to respond to axotomy and to the initial outgrowth of new optic axons. They only began to divide after the axons had reached the brain. Shortly afterwards, small numbers of Schwann cells began to leave the dividing pool and form myelin sheaths. More followed gradually, so that by 3 months remyelination was almost completed and few dividing cells were left. Moreover, remyelination occurred synchronously throughout the optic nerve, with the same time course in the pre-existing Schwann cells, the new ones that colonised the second injury, and the CNS oligodendrocytes elsewhere. The optic axons are the only common structures that could synchronise myelin formation in these disparate glial populations. The responses of the ectopic Schwann cells suggest that they are controlled by the regenerating optic axons in two consecutive steps. First, they begin to proliferate when the growing axons reach the brain. Second, they leave the cell cycle to differentiate individually at widely different times during the ensuing 2 months, during the critical period when the initial rough pattern of axon terminals in the optic tectum becomes refined into an accurate map. We suggest that each axon signals individually for myelin ensheathment once it completes this process.

Animals↗
PubMed2003

Identifying axon guidance defects in the embryonic zebrafish brain.

The method described here outlines a simple protocol to investigate the in vivo function of axon guidance molecules during the development of the embryonic zebrafish brain. By 24 hours postfertilization, a simple scaffold of axon tracts and commissures can be visualised in the brain using acetylated alpha-tubulin, a panaxonal marker that stains all axons. The highly stereotypical trajectory of axons in the embryonic zebrafish brain provides an ideal system in which to study the molecular mechanisms of axon guidance, as defects in the axon scaffold can be clearly visualised. We describe here our approach to identify defects in the trajectory of axons that establish the initial template of tracts in the embryonic fore- and mid-brain. By combining immunohistochemical techniques and confocal microscopy on dissected wholemounts of embryonic brains we are able to observe at high resolution the complete scaffold of axon tracts. This approach provides a rapid and simple means of assessing axon guidance defects in the developing brain. Given the advantages of the zebrafish as a model system, and the range of molecular perturbation methods now available, this technique provides a valuable tool for assessing the phenotypic effects of gene perturbations in a biologically relevant context.

Animals↗
PubMed2003

The number, size, and type of axons in rat subcortical white matter on left and right sides: a stereological, ultrastructural study.

Abundant evidence indicates important functional differences between the two cerebral hemispheres of humans, although the cellular basis of these differences is unknown. A recent hypothesis proposes that these functional differences depend on differences between sides in the "repertoire" of axonal conduction delays for cortico-cortical axons. In morphological terms this corresponds to differences in caliber, or proportion, of myelinated versus unmyelinated axons. Several behavioural studies have indicated that cerebral asymmetry occurs in rodents, in which rigorous morphological analysis is possible. The hypothesis was therefore tested for the first time in adult male Wistar rats, using transmission electron microscopy and stereological methods. Subcortical white matter was compared between left and right sides in three regions (frontal, parietal, and occipital). The average caliber and numerical density of unmyelinated and myelinated axons was compared between sides and between regions. All data were corrected for shrinkage. No significant differences between sides were found in the average caliber of either type of axon in any region. The numerical density of either type of axon also yielded no significant differences between sides in any region. Significant differences were evident between regions in both caliber and numerical density of the two axonal types, and these quantitative data are reported. The proportion of unmyelinated axons in the lateral white matter was also higher than in previous studies of hemispheric white matter that studied the corpus callosum. The present study provides no evidence supporting the hypothesis that functional hemispheric specialization is due to differences in axonal number, caliber or type.

Animals↗
PubMed1989

Target size regulates calibre and myelination of sympathetic axons.

Axons in vertebrate peripheral nerves are ensheathed by Schwann cells. For some axons, this sheath consists of a single layer of glial cell cytoplasm and plasma membranes; for other axons, Schwann cells form multilayered myelin. Whether or not a Schwann cell makes myelin is determined by a signal from the axon, but the nature of this signal is not known. Here I show that sympathetic postganglionic axons, which are normally not myelinated, become myelinated when their calibre is increased as a result of increasing the size of the peripheral target they innervate. This result implies that axon calibre, which is known to be correlated with myelination, is in fact the crucial determinant of whether an axon becomes myelinated. Furthermore, the finding that increasing or decreasing target size causes corresponding increases or decreases in axon size indicates that axon calibre is itself regulated by retrograde signals from peripheral target tissues.

Animals↗