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PubMed2002

NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors.

Several extracellular matrix (ECM) molecules have been identified as potent inhibitors of neurite outgrowth in vitro and are believed to limit axonal growth after CNS injury. Recent studies have shown that different members of the chondroitin sulfate proteoglycan (CSPG) class of putatively inhibitory ECM molecules are expressed after a number of CNS injuries. The purpose of this study was to evaluate the relative amounts of individual CSPGs expressed after spinal cord injury (SCI) and identify their cells of origin. Evaluation of total soluble CSPGs 2 weeks after dorsal column lesion in the rat demonstrated that NG2 is highly upregulated and is a major CSPG species. Immunocytochemical analysis further demonstrated that NG2 expression is upregulated within 24 hr of injury, peaks at 1 week, and remains elevated for at least an additional 7 weeks. NG2 expression results from a multicellular response to injury, including both reactive macrophages and oligodendrocyte progenitors; astrocytes were not identified as a major source of NG2. Immunocytochemical analysis of other CSPG family members 7 d after injury showed moderate upregulation of versican, brevican, and neurocan, and downregulation of phosphacan. Axonal tracing experiments demonstrated dense NG2 labeling adjacent to the forward processes of transected corticospinal tract axons in a spatial profile that could restrict axonal growth. Thus, NG2 is a major component of this putatively inhibitory class of ECM molecules expressed at sites of SCI and may restrict axonal regeneration.

Animals↗
PubMed1999

[Adhesive glycoproteins of the extracellular matrix].

Glycoproteins of the extracellular matrix and basement membrane play crucial role in cell recognition, adhesion, migration and proliferation. Morphogenesis and tissue and organ development in embryo, as well as healing processes in adults are dependent on the interactions of extracellular proteins with cell surface receptors. In this paper the structure and function of major adhesive proteins: fibronectin, tenascin, laminin and nidogen are reviewed. Recent data on the role of small leucine-rich and modular proteoglycans, such as decorin, biglycan, fibromodulin, versican, perlecan, neurocan, agrecan, agrin and other are given. Modifications of the expression and localization of extracellular glycoproteins in pathology are also presented.

Adult↗
PubMed2002

Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells.

Chondroitin sulfate proteoglycan (CS-PG) expression is increased in response to CNS injury and limits the capacity for axonal regeneration. Previously we have shown that neurocan is one of the CS-PGs that is upregulated (Asher et al., 2000). Here we show that another member of the aggrecan family, versican, is also upregulated in response to CNS injury. Labeling of frozen sections 7 d after a unilateral knife lesion to the cerebral cortex revealed a clear increase in versican immunoreactivity around the lesion. Western blot analysis of extracts prepared from injured and uninjured tissue also revealed considerably more versican in the injured tissue extract. In vitro studies revealed versican to be a product of oligodendrocyte lineage cells (OLCs). Labeling was seen between the late A2B5-positive stage and the O1-positive pre-oligodendrocyte stage. Neither immature, bipolar A2B5-positive cells, nor differentiated, myelin-forming oligodendrocytes were labeled. The amount of versican in conditioned medium increased as these cells differentiated. Versican and tenascin-R colocalized in OLCs, and coimmunoprecipitation indicated that the two exist as a complex in oligodendrocyte-conditioned medium. Treatment of pre-oligodendrocytes with hyaluronidase led to the release of versican, indicating that its retention at the cell surface is dependent on hyaluronate (HA). In rat brain, approximately half of the versican is bound to hyaluronate. We also provide evidence of a role for CS-PGs in the axon growth-inhibitory properties of oligodendrocytes. Because large numbers of OLCs are recruited to CNS lesions, these results suggest that OLC-derived versican contributes to the inhospitable environment of the injured CNS.

Animals↗
PubMed2001

Sprouting in the hippocampus after entorhinal cortex lesion is layer- specific but not translaminar: which molecules may be involved?

Entorhinal cortex lesion partially denervates the rat fascia dentata. This is said to induce sprouting of intact fibers from neighboring layers that invade the zone of the degenerating axons. However, recent in vivo and in vitro studies failed to demonstrate sprouting across laminar boundaries. Sprouting does occur, but it mainly involves unlesioned fiber systems terminating within the layer of fiber degeneration. These findings point to laminar cues that promote sprouting of fibers within the denervated zone while repelling other, adjacent fiber systems that try to grow into the denervated zone. A group of molecules that are likely to guide the sprouting process and the formation of borders are extracellular matrix molecules synthesized by reactive astrocytes. These molecules provide boundaries for growing axons during development. Some extracellular matrix molecules (tenascin-C, DSD- 1 -proteoglycan, neurocan, and brevican) were upregulated within the denervated outer molecular layer after lesion of the entorhinal cortex, suggesting a similar role after lesion. These extracellular matrix components forin a sharp molecular border towards the adjacent nondenervated inner molecular layer, and their pattern of distribution correlates precisely with the laminar termination pattern of the sprouting fiber populations. Thus, extracellular matrix molecules could delineate boundaries of axonal growth after entorhinal cortex lesion and could thus contribute to the molecular processes underlying the postlesional re-patterning of the fascia dentata.

Animals↗
PubMed2003

Different signals control laminar specificity of commissural and entorhinal fibers to the dentate gyrus.

The factors governing the characteristic laminated termination of hippocampal afferents are essentially unknown. Principally, diffusible factors of the target region, membrane-bound molecules on the ingrowing afferent fibers and on the postsynaptic target cells as well as molecules of the extracellular matrix (ECM), may play a role. Using slice cocultures as a model, we show that hyaluronic acid, an ECM molecule, is essential for the segregated, layer-specific termination of entorhinal fibers but not of commissural afferents to the mouse dentate gyrus. Laminar specificity of the latter, in contrast, is determined by the position of the postsynaptic granule cells. Thus, malpositioning of the granule cells in slice cultures from reeler mutant mice altered the projection of commissural fibers from cocultured wild-type hippocampus. In contrast, commissural fibers from reeler mouse hippocampus formed a normal, sharply delineated projection to the inner molecular layer of cocultured wild-type dentate gyrus, precluding a cell-autonomous effect of the reeler mutation on commissural neurons. Interestingly enough, entorhinal fibers formed their normal, sharply delineated projection in cocultured reeler dentate gyrus despite the malpositioning of the target granule cells. Because hyaluronan-associated molecules are likely to control the segregated termination of entorhinal fibers, we compared immunolabeling for neurocan and chondroitin sulfate in sections from reeler and wild-type mice and found it similar in both genotypes. Together these results show that different mechanisms underlie the formation of commissural and entorhinal fiber layers during the development of the dentate gyrus.

Animals↗
PubMed2003

Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: a balance of permissiveness and inhibition.

Increased expression of certain extracellular matrix (ECM) molecules after CNS injury is believed to restrict axonal regeneration. The chondroitin sulfate proteoglycans (CSPGs) are one such class of ECM molecules that inhibit neurite outgrowth in vitro and are upregulated after CNS injury. We examined growth responses of several classes of axons to this inhibitory environment in the presence of a cellular fibroblast bridge in a spinal cord lesion site and after a growth factor stimulus at the lesion site (fibroblasts genetically modified to secrete NGF). Immunohistochemical analysis showed dense labeling of the CSPGs NG2, brevican, neurocan, versican, and phosphacan at the host-lesion interface after spinal cord injury (SCI). Furthermore, robust expression of NG2, and to a lesser extent versican, was also observed throughout grafts of control and NGF-secreting fibroblasts. Despite this inhibitory milieu, several axonal classes penetrated control fibroblast grafts, including dorsal column sensory, rubrospinal, and nociceptive axons. Axon growth was amplified more in the presence of NGF-secreting grafts. Confocal microscopy demonstrated that axon growth was, paradoxically, preferentially associated with NG2-rich substrates in both graft types. NG2 expression also increased after sciatic nerve injury, wherein axons successfully regenerate. Cellular sources of NG2 in SCI and peripheral nerve lesion sites included Schwann cells and endothelial cells. Notably, these same cellular sources in lesion sites produced the cell adhesion molecules L1 and laminin, and these molecules all colocalized. Thus, axons grow along substrates coexpressing both inhibitory and permissive molecules, suggesting that regeneration is successful when local permissive signals balance and exceed inhibitory signals.

Animals↗
PubMed1988

Unstable thoracolumbar fractures, with emphasis on the burst fracture.

There is much controversy as to the appropriate treatment of unstable thoracolumbar fractures. If surgery is decided upon, this article suggests a plan to accomplish the reduction of the fracture and decompression of the neural elements. The fractures are divided into compression injuries, seat belt injuries, fracture-dislocations, and burst fractures. In each case the goal is to realign and stabilize the spine and allow adequate room for the spinal cord or the cauda equina. A burst fracture requires the most careful planning. Some decompression can be accomplished by distraction alone but impaction of the fragments posteriorly or removal of the fragments anteriorly may be required. The experience at the author's university has demonstrated that by using these techniques, the preoperative neurocanal compromise can be significantly improved over those series using posterior distraction alone. If canal compromise cannot be accomplished posteriorly, then anterior surgery is required.

Fractures, Bone↗
PubMed1994

Production and characterization of monoclonal antibodies to shark cartilage proteoglycan.

1. Two proteoglycans, PG1 and PG2, have been isolated from shark cartilage. Both are highly polydisperse and large (molecular mass: 1-10 x 10(6) Daltons) and contain chondroitin sulfate and keratan sulfate side chains, but PG2 is somewhat smaller than PG1 and contains less keratan sulfate. 2. Monoclonal antibodies were raised against PG1. Many antibodies were obtained and one of them, MST1, was subcloned and further characterized. This monoclonal antibody reacts with PG1 and PG2 from shark cartilage and also with aggrecan from bovine trachea cartilage. Chondroitinase AC-treated proteoglycans react with MST1, indicating that the antibody does not recognize chondroitin sulfate. MST1 also recognizes aggrecan from human cartilage and a proteoglycan from bovine brain (neurocan) but it does not recognize proteoglycans from rat Walker tumor, fetal calf muscle and decorin from human myoma. 3. Using MST1 we were able to demonstrate that both PG1 and PG2 aggregate with hyaluronic acid.

Animals↗
PubMed1994

Molecular cloning of brevican, a novel brain proteoglycan of the aggrecan/versican family.

To clone novel brain proteoglycans, we employed a strategy based on polyclonal antisera that recognize multiple proteoglycan core proteins. By using an antiserum raised against a fraction enriched for proteoglycans, we isolated three groups of cDNAs from a bovine brain lambda gt11 library. One of the cDNA groups has been fully sequenced and shown to encode a novel proteoglycan core protein of the aggrecan/versican family. This proteoglycan, named brevican, carries chondroitin sulfate chains, and, like other members of the family, contains a hyaluronic acid-binding domain in its N-terminal region, an epidermal growth factor-like repeat, a lectin-like and a complement regulatory protein-like domains in its C-terminal region. In contrast, the central region of brevican is much shorter than that of aggrecan, versican, or neurocan, and shows little homology with these proteoglycans. Brevican core protein exists as a 145 kDa full-length form and a 80 kDa N terminally truncated form. A significant amount of brevican devoid of any glycosaminoglycan chains is present in the brain, indicating that brevican is a "part-time" proteoglycan. Northern blot analysis reveals that a single 3.3-kilobase brevican transcript is present predominantly in the brain, and that it is expressed in primary cerebellar astrocytes but not in neurons.

Aggrecans↗
PubMed1996

Extracellular matrix in early cortical development.

Studies of the distribution and production of ECM components during development of the cerebral cortex have suggested several hypotheses regarding their functional role. In the earliest stages of cortical development, fibronectin is produced by cells in the ventricular zone throughout the telencephalic vesicle, where it may serve as a part of the local environment that supports cell division and determines cell fate. Fibronectin is also distributed along radial glial processes. It is closely associated with preplate neurons, as are chondroitin sulfate proteoglycans and several other ECM components. This association continues as preplate cells are divided into the marginal zone and subplate by the invasion of cortical plate neurons, suggesting that ECM, preplate cells and radial glia serve as a scaffold for cortical plate formation. Fibronectin is also produced by migrating neurons, but only by those moving into specific cortical domains, suggesting that it may help neurons destined for specific targets discriminate between adjacent glial guides. A recently defined ECM-like protein, reelin, is absent or abnormal in the reeler mutant mouse in which cortical neurons are severely malpositioned. Reelin is produced by marginal zone cells and is therefore appropriately located to serve as a stop signal for migrating neurons. Axons leaving the cortical plate cross the CSPG-rich subplate, then turn to follow a path containing much less CSPG. In contrast, the cortical trajectory of thalamic axons is centered on the subplate, indicating that CSPGs in the subplate are not a barrier to axon outgrowth and may instead be serving as guidance cues that distinguish afferent from efferent pathways. Neurocan, a CNS-specific CSPG with many molecular features that indicate roles in cell-cell and cell-substrate interactions, is the only CSPG defined to date whose distribution supports a role in distinguishing afferent from efferent pathways.

Animals↗
PubMed1996

The NG2 chondroitin sulfate proteoglycan: a multifunctional proteoglycan associated with immature cells.

In this review, we discuss the properties of the NG2 chondroitin sulfate proteoglycan, a structurally unique, integral membrane proteoglycan that is found on the surfaces of several different types of immature cells. NG2 is associated with multipotential glial precursor cells (O2A progenitor cells), chondroblasts of the developing cartilage, brain capillary endothelial cells, aortic smooth muscle cells, skeletal myoblasts and human melanoma cells. One common feature of these diverse cell types is that they retain the ability to divide throughout the life of the organism. The NG2 proteoglycan is a multifunctional protein; in vitro studies have shown that NG2 binds type VI collagen, interacts with and modulates the activity of the platelet-derived growth factor-alpha receptor, and inhibits neurite outgrowth. These functional properties are analogous to those of other proteoglycans such as syndecan, betaglycan, and neurocan, suggesting that structurally divergent proteoglycans can carry out similar functions within the organism.

Animals↗
PubMed1998

Ultrastructural localization of microfibrillar fibulin-1 and fibulin-2 during heart development indicates a switch in molecular associations.

The microfibrillar proteins fibulin-1 and fibulin-2 were previously identified as prominent components of the endocardial cushion tissue (ECT) during heart development and shown to persist in adult valves and septa. Immunogold staining has now been used to compare their localization in embryonic (days 9-11) and adult mouse heart with that of fibronectin and the chondroitin sulphate proteoglycan versican. All four proteins were deposited in the ECT, which consists of a hyaluronan-rich, mainly unstructured matrix, but were barely detectable in myocardial basement membranes or within endocardial cells. Digestion with hyaluronate lyase selectively released the fibulins and versican but not fibronectin from the ECT. Yet neither of the two fibulins bound to hyaluronan in solid-phase assays, in contrast to versican. In the adult heart valve, all four proteins could be detected close to cross-striated collagen fibrils or microfibrils, but only versican was lost upon exposure to hyaluronate lyase. The data indicate that fibulins are associated with the hyaluronan-matrix of ECT through a bridge of versican, but that this association changes upon valve development to another supramolecular, presumably microfibrillar organization based on fibronectin and/or fibrillins.

Age Factors↗
PubMed2004

Present situation and future aspects of spinal cord regeneration.

The central nervous system (CNS) has a limited capacity for regeneration after injury. In spinal cord injury (SCI) patients, total loss of all motor and sensory function occurs below the level of injury. Advances in treatment are expected for orthopedic and spinal surgeons. Recently, evidence of axonal regeneration and functional recovery has been reported in animal spinal cord injury models. Our studies on the roles of inhibitory molecules with a comparison between neonatal and adult animals may help serve as therapeutic targets to enhance axonal regeneration for the injured spinal cord. Also, our cell replacement study indicates the possibility of transplanting neural stem cells to supply the cell source for immature oligodendrocytes, which are thought to be essential for both the myelination and trophic support of regenerating axons in the spinal cord. Administration of neurotrophic factors, prevention of inhibitory factors, and stem cell technology have clinical applications in SCI patients. However, spinal cord regeneration involves a multistep process, and several factors have to be controlled after injury. A combination of several treatments could overcome a nonpermissive environment for spinal cord regeneration. Further understanding of the mechanisms and finding optimal targets of spinal cord regeneration are necessary to obtain successful therapies for SCI patients.

Animals↗
PubMed2004

Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle.

BACKGROUND: Survival and differentiation of neurons and the formation and maintenance of synapses in the cerebral cortex may be affected in schizophrenia. Since neurotrophins play an important role in these events, behavioral effects relevant to schizophrenia were investigated in rats that had compromised neurotrophin function during prefrontal cortical development. METHODS: Neonatal rat pups were injected into the developing prefrontal cortex with a depot preparation of p75 receptor antibody conjugated to saporin. Animals were tested for dopaminergic hyperresponsivity and prepulse inhibition of acoustic startle at 5 or 10 weeks. Neonatal and adult brain sections were examined for morphologic abnormality. RESULTS: Animals that received neonatal injections of p75 antibody conjugated to saporin showed significantly increased amphetamine-induced locomotion and rearing and impairment of prepulse inhibition of acoustic startle at 10 weeks of age but not at 5 weeks. Examination of adult brain sections revealed apparently normal structure, whereas neonatal brain sections showed apoptotic cells in the developing prefrontal cortex in pups that received p75 antibody conjugated to saporin. CONCLUSIONS: Compromised p75 neurotrophin receptor function in the developing prefrontal cortex may be associated with the manifestation of adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition and therefore may be involved in the pathogenesis of schizophrenia.

Acoustic Stimulation↗
PubMed1998

The core protein of the chondroitin sulfate proteoglycan phosphacan is a high-affinity ligand of fibroblast growth factor-2 and potentiates its mitogenic activity.

Using a radioligand binding assay we have demonstrated that phosphacan, a chondroitin sulfate proteoglycan of nervous tissue that also represents the extracellular domain of a receptor-type protein tyrosine phosphatase, shows saturable, reversible, high-affinity binding (Kd approximately 6 nM) to fibroblast growth factor-2 (FGF-2). Binding was reduced by only approximately 35% following chondroitinase treatment of the proteoglycan, indicating that the interaction is mediated primarily through the core protein rather than the glycosaminoglycan chains. Immunocytochemical studies also showed an overlapping localization of FGF-2 and phosphacan in the developing central nervous system. At concentrations of 10 microg protein/ml, both native phosphacan and the core protein obtained by chondroitinase treatment potentiated the mitogenic effect of FGF-2 (5 ng/ml) on NIH/3T3 cells by 75-90%, which is nearly the same potentiation as that produced by heparin at an equivalent concentration. Although studies on the role of proteoglycans in mediating the binding and mitogenic effects of FGF-2 have previously focused on cell surface heparan sulfate, our results indicate that the core protein of a chondroitin sulfate proteoglycan may also regulate the access of FGF-2 to cell surface signaling receptors in nervous tissue.

3T3 Cells↗
PubMed2004

Axon behaviour at Schwann cell - astrocyte boundaries: manipulation of axon signalling pathways and the neural adhesion molecule L1 can enable axons to cross.

Axon regeneration in vivo is blocked at boundaries between Schwann cells and astrocytes, such as occur at the dorsal root entry zone and around peripheral nerve or Schwann cell grafts. We have created a tissue culture model of these boundaries in Schwann cell - astrocyte monolayer co-cultures. Axon behaviour resembles that in vivo, with axons showing a strong preference for Schwann cells over astrocytes. At boundaries between the two cell types, axons growing on astrocytes cross readily onto Schwann cells, but only 15% of axons growing on Schwann cells are able to cross onto astrocytes. Treatment with chondroitinase or chlorate to reduce inhibition by proteoglycans did not change this behaviour. The neural adhesion molecule L1 is present on Schwann cells and not astrocytes, and manipulation of L1 by application of an antibody, L1-Fc in solution, or adenoviral transduction of L1 into astrocytes increased the proportion of axons able to cross onto astrocytes to 40-50%. Elevating cAMP levels increased crossing from Schwann cells onto astrocytes in live and fixed cultures, and had a co-operative effect with NT-3 but not with NGF. Inactivation of Rho with a cell-permeant form of C3 exoenzyme also increased crossing from Schwann cells to astrocytes. Our experiments indicate that the preference of axons for Schwann cells is largely mediated by the presence of L1 on Schwann cells but not astrocytes, and that manipulation of growth cone signalling pathways can allow axons to disregard boundaries between the two cell types.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Multiple defects in the formation of rat cortical axonal pathways following prenatal X-ray irradiation.

Prenatal X-ray irradiation is known to result in severe defects of neuronal migration and laminar formation in the cerebral cortex. We examined the formation of cortical afferent and efferent pathways in rats that had been exposed to X-ray irradiation (1.0 Gy) at embryonic day 14 (E14), by birthdating with bromodeoxyuridine (BrdU) and axonal labeling with 1-1'-dioctodecyl-3,3,3',3'- tetramethyl-indocarbocyanine perchlorate (DiI), in addition to immunohistochemical staining for various axonal markers including neurofilament, and cell adhesion molecules L1 and TAG-1. The results obtained were as follows. (i) The neuroepithelium formed germinal rosettes and concavities in the cortical anlage from 2 days after irradiation. Neurons generated in the neuroepithelium accumulated to form subcortical heterotopia and obstructed pathway formation in the intermediate zone, resulting in an aberrant trajectory of TAG-1-immunoreactive cortical efferent axons. (ii) In rats exposed to X-ray irradiation at E14, cystic cavities were formed in the cortex-striatum boundary region between E15 and E17, probably because of delayed cell death of neurons generated at E14. These cavities transiently interrupted both cortical afferent (L1-positive) and efferent (TAG-1-positive) axons. (iii) X-ray irradiation at E14 partially destroyed subplate neurons (transient targets of thalamic afferent axons) and disturbed the arrangement of the subplate layer. This resulted in a misrouting of neurofilament- and L1-immunoreactive thalamocortical axons that obliquely traversed the cortical plate to run up to the superficial layer. The present study demonstrates for the first time that X-ray irradiation during initial cortical development causes multiple defects in the formation of cortical afferent and efferent pathways.

Age Factors↗