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PubMed2000

Axon guidance at the midline of the developing CNS.

Bilaterally symmetric animals must be capable of transmitting information between the left and right sides of their body to integrate sensory input and to coordinate motor control. Thus, many neurons in the central nervous system (CNS) of a wide variety of higher organisms project so-called commissural axons across the midline. Interestingly, these axons are never observed to re-cross the midline. On the other hand, some neurons project axons that remain on their own (ipsilateral) side of the CNS, without ever crossing the midline. Recent studies demonstrate that specialized cells which reside at the ventral midline of the developing vertebrate spinal cord and Drosophila ventral nerve cord play critical roles in regulating the guidance of both crossing and non-crossing axons. For example, these cells secrete positively-acting guidance cues that attract commissural axons over long distances to the midline of the CNS. Furthermore, short-range interactions between guidance cues present on the surfaces of midline cells, and their receptors expressed on the surfaces of pathfinding axons, allow commissural axons to cross the midline and prevent ipsilaterally projecting axons from entering the midline. Remarkably, as commissural axons cross over to the opposite side of the CNS, the molecular composition of their surfaces is dynamically altered so that they become responsive to repulsive midline guidance cues that they had previously ignored. Thus, this exquisitely controlled guidance system prevents commissural axons from crossing the midline more than once. Strikingly, many of the molecular mechanisms that control midline guidance appear to be evolutionarily conserved.

Animals↗

PubMed1999

Effects of PMP22 duplication and deletions on the axonal cytoskeleton.

Axonal loss in Charcot-Marie-Tooth type 1A (CMT1A) is an important feature correlated with the functional disability in affected individuals. It is not known, however, how the most common genetic defect in Schwann cells (PMP22 duplication) causes the CMT1A phenotype and results in axonal loss. In this study, sural nerve segments from individuals with PMP22 duplications or deletions, causing the reciprocal disorder hereditary neuropathy with pressure palsies (HNPP), were grafted into the cut ends of the sciatic nerve of nude mice. The xenografts and host segments were studied at 2, 4, 6, 8, 12, and 16 weeks after grafting and compared with the controls from healthy volunteers. Within the CMT1A xenografts, the nude mice axons in the proximal part of the graft showed a significant increase in axonal area with an increase in the neurofilament and membranous organelle (mitochondria) density, compared with distal graft and distal host segments. A preferential distal axonal loss, associated with a perpetual axonal atrophy, degeneration, and axonal sprouting was observed over time, with increasing intensity at 8 to 16 weeks. These alterations were seen to a lesser extent in HNPP xenografts and were not observed in controls. In addition, the onset of regeneration-associated myelination was delayed, more significantly in HNPP xenografts than those of CMT1A. Our findings indicate that the PMP22 duplication in Schwann cells results in an impairment in the normal axonal cytoskeletal organization, resulting in distal axonal degeneration and fiber loss, and the affect of PMP22 deletion on axonal cytoskeleton is less deleterious.

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PubMed1983

The number and size of axons at the apex of the cat's canine tooth.

Using electron microscopy and morphometric analysis the number and size of axons entering the apex of the cat's mandibular canine tooth have been measured. The total number of axons varied from 761 to 1,903 between different animals but the maximum difference between right and left sides of the same animal was 353. From 56 to 79.6% of the axons were nonmyelinated; the difference in proportion between right and left sides never exceeded 6.4%. The mean circumference of myelinated axons ranged from 10.2 to 18.3 micrometers but again the right and left variation was much less and never exceeded 2 micrometers. In one tooth 38.8% of the myelinated axons were larger than 19 micrometers in circumference and thus outside the A delta range. The proportion was much smaller in other teeth but some "large" fibers were always present. Of all the nonmyelinated axons 19.7% showed some degree of axonal exposure to the extracellular space and 1.7% showed ax-oaxonal apposition. A small proportion of nonmyelinated axons showed evidence of apparent degeneration. Comparison of these data with those from studies at more coronal levels suggests that there is considerable branching and narrowing of fibers during their course through the dental pulp and that the degree of axonal exposure and apposition increases considerably. Some of the pulpal fibers are derived from larger axons than are normally associated with pain. The animal to animal variation in the parameters measured is considerable but right and left sides are similar.

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PubMed1991

Distribution and morphological characteristics of axons in the periodontal ligament of cat canine teeth and the changes observed after reinnervation.

The distribution and morphological characteristics of myelinated and non-myelinated axons innervating the lower canine periodontal ligament (PDL) in adult cats have been analysed. After perfusion fixation and decalcification, the teeth were slit transversely, divided into segments, and embedded in plastic. Ultrathin sections of each segment were examined in the electron microscope and used to reconstruct the whole PDL at 1, 4, 7, and 9 mm from the tooth apex. One millimeter from the tooth apex there were a mean of 920 myelinated axons and 1,415 non-myelinated axons. The numbers of axons declined toward the tooth crown. Bundles of myelinated and small non-myelinated axons lay adjacent to the blood vessels midway between the bone and cementum. Isolated myelinated axons appeared to have split away from these main nerve bundles and entered the avascular zone of the ligament, where they lost their myelin sheaths to become large non-myelinated axons rich in mitochondria. These non-myelinated axons sometimes appeared to be linked to collagen fibres and were thought to be the mechanoreceptor terminals. Twelve weeks after sectioning and inferior alveolar nerve, the total number of axons innervating the periodontal ligament was 50% of that found in the contralateral controls. The large non-myelinated axons had smaller mean diameters and contained fewer mitochondria, a change which may be consistent with a reduction in mechanoreceptor excitability.

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PubMed2003

Sorting and convergence of primary olfactory axons are independent of the olfactory bulb.

Primary olfactory axons expressing the same odorant receptor gene sort out and converge to fixed sites in the olfactory bulb. We examined the guidance of axons expressing the P2 odorant receptor when they were challenged with different cellular environments in vivo. In the mutant extratoes mouse, the olfactory bulb is lacking and is replaced by a fibrocellular mass. In these animals, primary olfactory axons form glomerular-like loci despite the absence of normal postsynaptic targets. P2 axons are able to sort out from other axons in this fibrocellular mass and converge to form loci of like axons. The sites of these loci along mediolateral and ventrodorsal axes were highly variable. Similar convergence was observed for larger subpopulations of axons expressing the same cell surface carbohydrates. The sorting out and convergence of like axons also occurred during regeneration following bulbectomy. Olfactory axon behaviour in these models demonstrates that sorting and convergence of axons are independent of the target, which instead provides distinct topographic cues for guidance.

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PubMed2004

Sema3A regulates the timing of target contact by cranial sensory axons.

The trigeminal ganglion provides the somatosensory innervation for the anterior rat tongue. At early embryonic stages (embryonic day [E] 12-13) pre-tongue explants repel trigeminal axon outgrowth, and this is mediated by Sema3A (Rochlin and Farbman [1998] J. Neurosci. 18:6840-6852; Rochlin et al. [2000] J. Comp. Neurol. 422:579-593). Despite a decrease in repulsion by E14 and older tongue explants, Sema3A mRNA persists throughout the dorsal epithelium through E18, after axons have begun to penetrate papilla epithelium. We investigated the hypothesis that Sema3A continues to act as a repellent and that subpopulations of trigeminal axons that penetrate the epithelium become unresponsive to Sema3A. Sema3A repelled trigeminal axons in vitro regardless of the neurotrophic factor used to stimulate axon outgrowth, but the minimum level of Sema3A required to repel depended on the neurotrophic factor. Thus, in vitro, trigeminal axons are repelled by Sema3A when they would be penetrating the Sema3A-mRNA rich epithelium in vivo. Whereas dorsal epithelium on tongue explants dissected at stages preceding target contact (E15) repelled trigeminal axons in vitro, explants dissected at later stages (E18), after axons would have penetrated the epithelium in vivo, were not repellent. To determine whether Sema3A prevents premature target penetration in vivo, we assessed the timing of target contact by sensory axons in Sema3A-/minus; and +/+ mice. Contact of the epithelium occurs prematurely in Sema3A-/minus; mice, but not penetration. Taken together, our data imply that Sema3A acts as a short-range repellent that regulates the timing of target contact by trigeminal axons.

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PubMed2005

Pathway sampling by regenerating peripheral axons.

A century ago, Ramon y Cajal described the generalized response of regenerating peripheral axons to their environment. By using mice that express fluorescent proteins in their axons, we are now able to quantify the response of individual axons to nerve transection and repair. Sciatic nerves from nonexpressing mice were grafted into those expressing a yellow variant of green fluorescent protein, then examined at 5, 7, or 10 days after repair. Regeneration was found to be a staggered process, with only 25% of axons crossing the repair in the first week. In the setting of Wallerian degeneration, this stagger will expose growth cones to an evolving menu of molecular cues upon which to base pathway decisions. Many axons arborize, allowing them to interact simultaneously with several pathways. Arborization could serve as the anatomical substrate for specificity generation through collateral pruning. Axons often travel laterally across the face of the distal stump before choosing a pathway. As a result, the average unbranched axon has access to over 100 distal Schwann cell tubes. This extensive access, however, does not ensure correct matching of axon and end organ, suggesting that pathway choice is made on the basis of factors other than end organ identity. These observations explain the failure of refined surgical techniques to restore normal function after nerve injury. The apparent wandering of axons across the repair defies surgical control and mandates a biological approach to reuniting severed axons with appropriate distal pathways.

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PubMed2005

Olfactory marker protein modulates primary olfactory axon overshooting in the olfactory bulb.

Olfactory marker protein (OMP) is expressed by mature primary olfactory sensory neurons during development and in adult mice. In mice that lack OMP, olfactory sensory neurons have perturbed electrophysiological activity, and the mice exhibit altered responses and behavior to odor stimulation. To date, defects in axon guidance in mice that lack OMP have not been investigated. During development of the olfactory system in mouse, primary olfactory axons often overshoot their target glomerular layer and project into the deeper external plexiform layer. These aberrant axonal projections are normally detected within the external plexiform layer up to postnatal day 12. We have examined the projections of primary olfactory axons in OMP-tau:LacZ mice and OMP-GFP mice, two independent lines in which the OMP coding region has been replaced by reporter molecules. We found that axons overshoot their target layer and grow into the external plexiform layer in these OMP null mice as they do in wild-type animals. However, in the absence of OMP, overshooting axons are more persistent and remain prominent until 5 weeks postnatally, after which their numbers decrease. Overshooting axons are still present in these mice even at 8 months of age. In heterozygous mice, axons also overshoot into the external plexiform layer; however, there are fewer axons, and they project for shorter distances, compared with those in a homozygous environment. Our results suggest that perturbed electrophysiological responses, caused by loss of OMP in primary olfactory neurons, reduce the ability of primary olfactory axons to recognize their glomerular target.

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PubMed2006

Degradation of chondroitin sulfate proteoglycans potentiates transplant-mediated axonal remodeling and functional recovery after spinal cord injury in adult rats.

Transplantation of growth-permissive cells or tissues was used to bridge a lesion cavity and induce axonal growth in experimental spinal cord injury (SCI). Axonal interactions between host and transplant may be affected by upregulation of inhibitory chondroitin sulfate proteoglycans (CSPGs) following various transplantation strategies. The extent of axonal growth and functional recovery after transplantation of embryonic spinal cord tissue decreases in adult compared to neonatal host. We hypothesized that CSPGs contribute to the decrease in the extent to which transplant supports axonal remodeling and functional recovery. Expression of CSPGs increased after overhemisection SCI in adult rats but not in neonates. Embryonic spinal cord transplant was surrounded by CSPGs deposited in host cord, and the interface between host and transplant seemed to contain a large amount of CSPGs. Intrathecally delivered chondroitinase ABC (C'ase) improved recovery of distal forelimb usage and skilled motor behavior after C4 overhemisection injury and transplantation in adults. This behavioral recovery was accompanied by an increased amount of raphespinal axons growing into the transplant, and raphespinal innervation to the cervical motor region was promoted by C'ase plus transplant. Moreover, C'ase increased the number of transplanted neurons that grew axons to the host cervical enlargement, suggesting that degradation of CSPGs supports remodeling not only of host axons but also axons from transplanted neurons. Our results suggest that CSPGs constitute an inhibitory barrier to prevent axonal interactions between host and transplant in adults, and degradation of the inhibitory barrier can potentiate transplant-mediated axonal remodeling and functional recovery after SCI.

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PubMed1981

Developmental growth and degeneration of pulpal axons in feline primary incisors.

The life history of pulpal axons in primary mandibular incisors was examined by light and electron microscopy in 56 kittens aged from 25 days postconception to 120 days after birth. Cells resembling Schwann cells preceded the first arrival of pulpal axons, 1 week postnatally. myelination was initiated during the second week. Two months after birth the incisors were fully grown and each pulp contained about 100 axons. Between 10 and 20% of these were myelinated and ranged in size from 1 to 5 micrometer. The relation between number of myelin lamellae and axon size appeared nonlinear and differed markedly from that in similarly sized inferior alveolar nerve axons. During the third month many unmyelinated axons showed signs of degeneration. With progress of root resorption an increasing proportion of both unmyelinated and myelinated axons degenerated. In highly resorbed incisors necrotic Schwann cells were associated with degenerating axons and there was a generalized pulpal tissue reaction. In some teeth with advanced root resorption pulpal axons were lacking. A progressive derangement of all pulpal tissue elements continued until shedding during the second half of the fourth month. In incisor nerve branches below the incisor teeth axon degeneration was very limited.

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PubMed1986

Postnatal changes in arborization patterns of murine retinocollicular axons.

The growth and arborization of murine retinocollicular axons have been studied by means of HRP axon filling during postnatal development. Transformations in arborization patterns have been correlated with changes in synaptic density in the superficial collicular neuropil and with the formation of synapses by HRP-filled axons. At all postnatal ages axons of the optic projection are fasciculated and most follow a rostrocaudally aligned path. On the day of birth the axons course through both stratum griseum superficiale (SGS) and stratum opticum (SO); during the following 4 days the axon trunks disappear from SGS and are subsequently found only in SO. From postnatal day (P) 0 to P3, the majority continue far caudally in the colliculus, giving rise to small ascending collaterals at multiple points along their course. Ultimately, usually by P3, one or two collaterals begin to branch profusely and by P5 the majority of axons give rise to a focal terminal ascending arborization. The general configuration of most arborizations at P3 approximates that of the mature axon. However, the richness of terminal branching increases from P3 through the first 2 postnatal weeks. Synaptic density is relatively low in the first postnatal week, and no synapses involving HRP-filled optic axons were identified in this interval. Subsequently, after elaboration of definitive arbors has begun, synaptogenesis in the surrounding neuropil accelerates. Synaptic density in the upper SGS approximates adult values early in the third postnatal week. By this time synaptic junctions involving the terminal arborizations of optic axons are abundant.

Aging↗

PubMed1986

Gap-junctional contacts of luminosity-type horizontal cells in the carp retina: a novel pathway of signal conduction from the cell body to the axon terminal.

L-type horizontal cells (271) of the carp retina were studied with the aid of intracellular injections of Lucifer yellow and horseradish peroxidase (HRP). Coupling among these cells was revealed by passage of the dye out of the injected cell. Thick processes that crossed axons filled with Lucifer yellow also contained the stain. These thick processes appear to be the axon terminals of other horizontal cells. Serial reconstruction of an axon terminal by electron microscopy revealed two groups of elements connected to the axon terminal with putative gap junctions. One large-diameter group was identified as axon terminals of other cells. From the results of the Lucifer dye-coupling experiments, the smaller-diameter elements are thought to be the axons of other horizontal cells. Thus, the axon terminals of carp horizontal cells have putative gap-junctional contacts not only with other axon terminals but also with the axons of other horizontal cells. This newly discovered connection could serve as a pathway for signal transfer between the cell body and the axon terminal of different horizontal cells.

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PubMed1990

Axonal regrowth in the amyelinated optic nerve of the myelin-deficient rat: ultrastructural observations and effects of ganglioside administration.

It has been postulated that myelin degradation products may inhibit regrowth of mammalian central axons and that central nervous system (CNS) myelin and oligodendrocytes may constitute a "nonpermissive substrate" for axonal growth. To address these issues, we utilized an X-linked rat mutant, myelin-deficient or md. In the optic nerve of this mutant, 40 days and more postnatally, normal myelin is absent and oligodendrocytes are few (Dentinger et al. Brain Res. 344:255-266, 1985). Twenty-eight days before sacrifice, we operated on four groups of 50-day-old md rats and age-matched normal littermates according to the following protocols: 1) unilateral intraorbital optic nerve crush; 2) beginning within 1 hour of nerve crush, daily intraperitoneal injection of GM1 ganglioside (20 mg/kg) dissolved in phosphate-buffered saline (PBS); 3) daily intraperitoneal injection of PBS alone, also begun within 1 hour of nerve crush; 4) severance of the optic nerve immediately behind the papilla 16 or 21 days after the primary crush lesions. Additionally, normal and md rats were killed 4 and 14 days after unilateral optic nerve injury. Nerves of unoperated md rats and their normal littermates were also processed. In the operated animals that did not receive GM1, ultrastructural analysis 4, 14, and 28 days after lesioning revealed that md optic nerves contained significantly greater numbers of regenerating axons, including growth cones and varicosities, than nerves of normal rats. Notably, 28 days postoperatively, (group 1), regenerating axons were still abundant in md nerve, whereas, in nerves of normally myelinated littermates, axonal numbers were diminished markedly. Regenerating optic axons of both md and normally myelinated rats were oriented by linear astrocytic arrays and often were enclosed by astrocytic cytoplasm. In normal littermates, GM1 administration (group 2) induced a significant increase in the number of axons within the operative lesion. Paradoxically, GM1 inhibited the ordinarily robust regeneration of md axons. PBS-injected md and normal rats (group 3) showed no significant differences from noninjected, operated animals. Severance of the nerve at the papilla (group 4) 7-12 days before sacrifice confirmed the origination of axonal regrowth by retinal ganglion cells. The data provide in vivo support for a role of myelin breakdown products or the secretory products of oligodendroglia in the inhibition of regenerative axonal sprouting within mammalian CNS.

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PubMed1991

Synapses made by axons of callosal projection neurons in mouse somatosensory cortex: emphasis on intrinsic connections.

This is one of a series of papers aimed at identifying the synaptic output patterns of the local and distant projections of subgroups of pyramidal neurons. The subgroups are defined by the target site to which their main axon projects. Pyramidal neurons in areas 1 and 40 of mouse cerebral cortex were labeled by the retrograde transport of horseradish peroxidase (HRP) transported from severed callosal axons in the contralateral hemisphere. Terminals of the local axon collaterals of these neurons ("intrinsic" terminals) were identified in somatosensory areas 1 and 40, and their distribution and synaptic connectivity were examined. Also examined were the synaptic connections of "extrinsic" callosal axon terminals labeled by lesion induced degeneration consequent to the severing of callosal fibers. A post-lesion survival time of 3 days was chosen because by this time the extrinsic terminals were all degenerating, whereas the intrinsic terminals were labeled by HRP. Both intrinsic and extrinsic callosal axon terminals occurred in all layers of the cortex where they formed only asymmetrical synapses. Layers II and III contained the highest concentrations of both types of callosal axon terminal. Analyses of serial thin sections through layers II and III in both areas 1 and 40 yielded similar results: 97% of the extrinsic (277 total sample) and of the intrinsic (1215 total sample) callosal axon terminals synapsed onto dendritic spines, likely those of pyramidal neurons; the remainder synapsed onto dendritic shafts of both spiny and nonspiny neurons. Thus the synaptic output patterns of intrinsic vs. extrinsic callosal axon terminals are strikingly similar. Moreover, the high proportion of axospinous synapses formed by both types of terminal contrasts with the proportion of asymmetrical, axospinous synapses that occur in the surrounding neuropil where only about 80% of the asymmetrical synapses are onto spines. This result is in accord with previous quantitative studies of the synaptic connectivities of both extrinsic and intrinsic axonal pathways in the cortex (White and Keller, 1989: Cortical Circuits; Boston: Birkhauser): in all instances, axonal pathways are highly selective for the types of elements with which they synapse.

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PubMed1993

NILE/L1 and NCAM-polysialic acid expression on growing axons of isolated neurons.

The neuron adhesion molecules NILE/L1 and NCAM may be involved in axonal guidance and cell recognition. To investigate all exposed membrane domains of single neurons, something which has not previously been done for any adhesion molecule, we used digitally processed scanning electron microscopy with a high-energy backscatter electron detector. This allowed a quantitative analysis of immunogold staining densities on all surfaces of isolated rat hippocampal neurons in culture to study NILE/L1 and NCAM expression independent of potentially inductive innervation. During early stages of neuritic extension, all growth cones showed similar NILE/L1 expression, but as soon as a single process extended farther than the others (by 20 hours), this putative axon and its growth cone generally showed a stronger level of NILE/L1 immunogold labeling than the other neurites. This is the earliest evidence of plasma membrane differentiation between axons and dendrites. With further neuritic growth, the relative NILE/L1 expression on axons and their growth cones continued to increase. In contrast to some earlier reports, NILE/L1 was expressed on axonal growth cones growing on both polylysine-coated glass and astrocyte substrates. Strong immunostaining for NCAM-related polysialic acid (PSA) was found on axonal growth cones and filopodia, suggesting that the homophilic adhesive action of NCAM may be reduced during axonal growth. PSA showed greater labeling on distal axons than on other areas of the neuron, indicating a variable NCAM-mediated adhesion on different regions of the same cell. Neither NILE/L1, NCAM, nor PSA appeared to show regional differences in axons fasciculating or defasciculating on themselves. A strong intercellular heterogeneity of NILE/L1, NCAM, and PSA expression levels on neurons in the same culture dish was found, suggesting that subsets of cells from the hippocampus may express biologically relevant differences in adhesion molecules compared to neighboring neurons. In light of the growing body of evidence pointing to the multifaceted array of homophilic and heterophilic binding interactions that NILE/L1 and NCAM may exhibit, and the functional importance of molecular densities, the quantitative data here support the hypothesis that sufficient cellular and subcellular heterogeneity exists for these molecules to be involved in some aspects of axonal guidance.

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PubMed1994

Glial domains and axonal reordering in the chiasmatic region of the developing ferret.

This study has examined the developing glial architecture of the optic pathway and has related this to the changing organization of the constituent axons. Immunocytochemistry was used to reveal the distribution of glial profiles, and DiI was used to label either radial glial profiles or optic axons. Electron microscopy was used to determine the distribution of glial profiles, axons, growth cones, and wrists at different locations along the pathway. Three different glial boundaries were defined: Two of these are revealed as changes in the distribution of vimentin-immunoreactive profiles occurring in the prechiasmatic optic nerve and at the threshold of the optic tract, respectively, and one by the presence of glial fibrillary acidic protein (GFAP)-immunoreactive profiles at the chiasmatic midline. The latter, midline boundary may be related to the segregation of nasal from temporal optic axons. The boundary at the threshold of the optic tract coincides with the segregation of dorsal from ventral optic axons that emerges at this location in the pathway. The segregation of old from young optic axons is shown to occur only gradually along the pathway. Glial profiles are most frequent in the deeper parts of the tract, coursing parallel to the optic axons and orthogonal to their usual radial axis. These are suggested to arise from later-growing radial glial fibers that are diverted to grow amongst the older optic axons. Those glial profiles may subsequently impede axonal invasion, thus creating the chronotopic reordering by forcing the later-arriving axons to accumulate superficially.

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PubMed1995

Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts I. Neural cell adhesion molecules.

To gain insight into the possible molecular mechanisms underlying axonal regeneration of neurons of the adult central nervous system (CNS), we have investigated, by in situ hybridization and by immunocytochemistry, the localization and sites of synthesis of the neurite outgrowth-promoting cell surface molecules L1, N-CAM and its highly sialylated form, N-CAM-PSA, in and around peripheral nerve grafts implanted into the thalamus of adult rats. Normal unoperated adult rat thalamus contains N-CAM and L1 but no N-CAM-PSA immunoreactive axons. Between 7 days and 13 weeks after graft implantation, L1, N-CAM and N-CAM-PSA were all present at the surface of axonal sprouts in the brain parenchyma close to grafts and in the central parts of Schwann cell columns within grafts. Schwann cell membranes were L1 and N-CAM positive at all postgraft survival times, more strongly at 2-4 weeks than other times, but were associated with N-CAM-PSA reaction product only where they abutted N-CAM-PSA positive axons. Schwann cell membranes apposed to basal laminae (which were avoided by regenerating CNS axons) were L1, N-CAM and N-CAM-PSA negative. Between 3 days and 8 weeks after grafting, N-CAM and L1 mRNA were generally weakly upregulated in neurons of the ipsilateral thalamus, but, most conspicuously, L1 mRNA was strongly upregulated in the neurons of the thalamic reticular nucleus; these neurons are known to regenerate axons very effectively into peripheral nerve grafts and are the probable source of most of the axons which enter thalamic grafts. N-CAM and L1 mRNA were also strongly upregulated in presumptive Schwann cells in the graft. These results show that regenerating CNS axons (re)express N-CAM-PSA and upregulate L1 and N-CAM, suggesting that all of these molecules may play a role in cellular interactions during the regeneration of CNS axons. Furthermore L1 synthesis appears to be particularly well correlated with the ability of CNS neurons to regenerate axons into peripheral nerve grafts.

Animals↗

PubMed1995

Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts. II. Tenascin-C.

Tenascin-C is a developmentally regulated extracellular matrix component. There is evidence that it may be involved in axon growth and regeneration in peripheral nerves. We have used in situ hybridization and immunocytochemistry to investigate the association of tenascin-C with central nervous system axons regenerating through a peripheral nerve autograft inserted into the thalamus of adult rats. Between 3 days and 4 weeks after implantation, tenascin-C immunoreactivity was increased in the grafts, first at the graft/brain interface, then in the endoneurium of the graft, and finally within the Schwann cell columns of the graft. By electron microscopy, reaction product was present around collagen fibrils and basal laminae in the endoneurium, but the heaviest deposits were found at the surface of regenerating thalamic axons within Schwann cell columns. Schwann cell surfaces were not associated with tenascin-C reaction product except where they faced the tenascin-rich basal lamina or were immediately opposite axons surrounded by tenascin-C. By 8 weeks after graft implantation tenascin-C in the endoneurium and around axons of the graft was decreased. In the brain parenchyma around the proximal part of the graft, axonal sprouts associated with tenascin-C could not be identified earlier than 2 weeks after grafting and were sparse at this stage. Larger numbers of such axons were present at 8-13 weeks after grafting and were located predominantly where the glia limitans between brain and graft appeared to be incomplete, suggesting that the tenascin-C may have penetrated the brain parenchyma from the graft. By in situ hybridization, cells expressing tenascin-C mRNA (probably Schwann cells) appeared first at the brain/graft interface 3 days after grafting and thereafter were mainly located within the grafts. Lightly labelled cells containing tenascin-C mRNA (probably glial cells) were scattered in the thalamic parenchyma both ipsilateral and contralateral to the graft and a few heavily labelled cells were located very close to the tip of the graft. These results show that regenerating adult thalamic axons, unlike regenerating peripheral axons, become intimately associated with peripheral nerve graft-derived tenascin-C, suggesting that they express a tenascin-C receptor, as many neurons do during development, and that tenascin-C derived from Schwann cells may play a role in the regenerative growth of such axons through the grafts.

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