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PubMed2007

ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth-inhibitory chondroitin sulfate proteoglycans.

Inhibition of Rho-kinase (ROCK) with Y27632 stimulates sprouting by injured corticospinal tract and dorsal column tract axons, and accelerates functional recovery. However, regeneration of these axons across the glial scar was not observed. Here we examined the effects of Y27632 treatment on chondroitin sulfate proteoglycan (CSPG) expression by astrocytes, which are a key component of the reactive gliosis inhibiting axonal regeneration. In vivo, rats underwent a dorsal column transection and were treated with Y27632 via intrathecal pump infusion. Compared with controls, Y27632-treated injury sites displayed exaggerated upregulation of glial fibrillary acid protein and neurocan immunoreactivity along the lesion edge. In vitro, astrocytes assumed a reactive morphology (stellate shape) and increased their expression of CSPGs after Y27632 treatment. Neurite growth by dissociated cortical neurons decreased when cultured on the extracellular matrix (ECM) derived from Y27632-treated astrocytes. This decrease in neurite growth was reversed with chondroitinase-ABC (ChABC) digestion, indicating that the inhibition was due to CSPG depositions within the ECM. Interestingly, conditioned medium (CM) from untreated astrocytes was inhibitory to neurite growth, which was overcome by ChABC digestion. Such inhibitory activity was not found in the CM of Y27632-treated astrocytes. Taken together, these data support a model where ROCK inhibition by Y27632 modifies astrocytic processing of CSPGs, and increases the presence of CSPGs within the ECM while reduces CSPGs in the CM (cerebrospinal fluid in vivo). This increased expression of inhibitory CSPGs in the ECM of the glial scar may counteract the growth promoting effects of ROCK inhibition on axonal growth cones.

Amides↗
PubMed1998

Formation of postsynaptic-like membranes during differentiation of embryonic stem cells in vitro.

To analyze the formation of neuromuscular junctions, mouse pluripotent embryonic stem (ES) cells were differentiated via embryoid bodies into skeletal muscle and neuronal cells. The developmentally controlled expression of skeletal muscle-specific genes coding for myf5, myogenin, myoD and myf6, alpha 1 subunit of the L-type calcium channel, cell adhesion molecule M-cadherin, and neuron-specific genes encoding the 68-, 160-, and 200-kDa neurofilament proteins, synaptic vesicle protein synaptophysin, brain-specific proteoglycan neurocan, and microtubule-associated protein tau was demonstrated by RT-PCR analysis. In addition, genes specifically expressed at neuromuscular junctions, the gamma- and epsilon-subunits of the nicotinic acetylcholine receptor (AChR) and the extracellular matrix protein S-laminin, were found. At the terminal differentiation stage characterized by the formation of multinucleated spontaneously contracting myotubes, the myogenic regulatory gene myf6 and the AChR epsilon-subunit gene, both specifically expressed in mature adult skeletal muscle, were found to be coexpressed. Only the terminally differentiated myotubes showed a clustering of nicotinic acetylcholine receptors (AChR) and a colocalization with agrin and synaptophysin. The formation of AChRs was also demonstrated on a functional level by using the patch clamp technique. Taken together, our results showed that during ES cell differentiation in vitro neuron- and muscle-specific genes are expressed in a developmentally controlled manner, resulting in the formation of postsynaptic-like membranes. Thus, the embryonic stem cell differentiation model will be helpful for studying cellular interactions at neuromuscular junctions by "loss of function" analysis in vitro.

Agrin↗
PubMed1994

Complete coding sequence, deduced primary structure, chromosomal localization, and structural analysis of murine aggrecan.

We have isolated and sequenced overlapping cDNA clones encoding the entire core protein of aggrecan (the large aggregating chondroitin sulfate/keratan sulfate proteoglycan of cartilage) from three chondrocyte cDNA libraries of BALB/c mice and localized the aggrecan gene in mouse chromosome 7. We determined 7386 bp of the cDNA sequence, including 132 and 854 nucleotides of 5' and 3' untranslated regions, respectively. The core protein precursor is 2132 amino acids long (M(r) 222,008), including a 19-residue secretory signal peptide. The overall amino acid sequence of the mouse aggrecan shows 91.6% identity to rat and 72.5% to human aggrecan. Comparison of the amino acid sequences of various domains and subdomain structures of mouse aggrecan to known sequences of other species and related proteins (versican, neurocan, link protein, and lymphocyte homing receptor CD44) revealed high levels of identity of the G1, G2, and G3 globular domains and relatively less conserved structures in the interglobular and glycosaminoglycan-attachment regions. Epidermal growth factor (EGF)-like module was detected in only a minor fraction of aggrecan clones, while the complement regulatory protein (CRP)-like domain was regularly expressed in all samples.

Aggrecans↗
PubMed2001

Inhibitory proteoglycan immunoreactivity is higher at the caudal than the rostral Schwann cell graft-transected spinal cord interface.

To begin to evaluate the influence that proteoglycans may have on the success of Schwann cell (SC) transplants to induce axonal regrowth across a complete transection lesion and beyond, we determined the pattern of expression of inhibitory chondroitin sulfate proteoglycans (CSPGs) 3 weeks after transplantation into completely transected adult rat thoracic spinal cord. Using immunohistochemistry, we observed that: (1) CSPGs recognized by CS-56 antibody are present on astrocytes, fibroblasts, and SCs in the distal graft, and at lesion and cystic cavity borders; (2) CS-56 immunoreactivity (IR) is greater at the caudal SC graft-host cord interface than the rostral interface; (3) phosphacan-IR, also greater at the caudal interface, is associated with astrocytes, fibroblasts, as yet unidentified cells, and extracellular matrix; (4) neurocan-IR is present on astrocytes and as yet unidentified cells in grey and white matter; and (5) NG2-IR is associated with matrix near SC grafts, unidentified cells mainly in white matter, and lesion borders and cysts. Neither oligodendrocytes nor activated macrophages/microglia were immunostained. In sum, the CSPGs studied are increased at 3 weeks, especially at the caudal SC graft-cord interface, possibly contributing to an inhibitory molecular barrier that precludes regrowing descending axons from entering the caudal host cord.

Animals↗
PubMed2002

Inhibition of axon growth by oligodendrocyte precursor cells.

The glial scar that forms at the site of injury is thought to be a biochemical and physical barrier to successful regeneration, although the molecules responsible for this barrier function are not well understood. Glia scars contain large numbers of oligodendrocyte precursor cells (OPCs) and these cells can produce several different growth-inhibitory chondroitin sulfate proteoglycans (CSPGs), including NG2, neurocan, and phosphacan. Here, we used membrane-based assays to show that the surface of OPCs is both nonpermissive and inhibitory for neurite outgrowth. Inhibition of growth by OPC is reversed by treatment with antibodies against the NG2 CSPG and the expression of NG2 is sufficient to change a growth-permissive cell surface to a nonpermissive surface. These result suggest that the OPCs that accumulate rapidly at sites of CNS injury can contribute to the creation of an environment that inhibits nerve regeneration and that NG2 is a necessary feature of that environment.

Animals↗
PubMed2000

Lecticans: organizers of the brain extracellular matrix.

Lecticans are a family of chondroitin sulfate proteoglycans, encompassing aggrecan, versican, neurocan and brevican. These proteoglycans are characterized by the presence of a hyaluronan-binding domain and a C-type lectin domain in their core proteins. Through these domains, lecticans interact with carbohydrate and protein ligands in the extracellular matrix and act as linkers of these extracellular matrix molecules. In adult brain, lecticans are thought to interact with hyaluronan and tenascin-R to form a ternary complex. We propose that the hyaluronan-lectican-tenascin-R complex constitutes the core assembly of the adult brain extracellular matrix, which is found mainly in pericellular spaces of neurons as 'perineuronal nets'.

Alternative Splicing↗
PubMed2006

Differential expression of several molecules of the extracellular matrix in functionally and developmentally distinct regions of rat spinal cord.

We have examined the regional distribution of several chondroitin sulfate proteoglycans (neurocan, brevican, versican, aggrecan, phosphacan), of their glycosaminoglycan moieties, and of tenascin-R in the spinal cord of adult rat. The relationships of these molecules with glial and neuronal populations, identified with appropriate markers, were investigated by using multiple fluorescence labeling combined with confocal microscopy. The results showed that the distribution of the examined molecules was similar at all spinal cord levels but displayed area-specific differences along the dorso-ventral axis, delimiting functionally and developmentally distinct areas. In the gray matter, laminae I and II lacked perineuronal nets (PNNs) of extracellular matrix and contained low levels of chondroitin sulfate glycosaminoglycans (CS-GAGs), brevican, and tenascin-R, possibly favoring the maintenance of local neuroplastic properties. Conversely, CS-GAGs, brevican, and phosphacan were abundant, with numerous thick PNNs, in laminae III-VIII and X. Motor neurons (lamina IX) were surrounded by PNNs that contained all molecules investigated but displayed various amounts of CS-GAGs. Double-labeling experiments showed that the presence of PNNs could not be unequivocally related to specific classes of neurons, such as motor neurons or interneurons identified by their expression of calcium-binding proteins (parvalbumin, calbindin, calretinin). However, a good correlation was found between PNNs rich in CS-GAGs and the neuronal expression of the Kv3.1b subunit of the potassium channel, a marker of fast-firing neurons. This observation confirms the correlation between the electrophysiological properties of these neurons and the specific composition of their microenvironment.

Animals↗
PubMed2000

Distribution of testican expression in human brain.

Testican is a putative extracellular heparan/ chondroitin sulfate proteoglycan of unknown function that is expressed in a variety of human tissues at widely different levels but is most abundant in the brain. In mice, testican mRNA has been detected only in brain and it is therefore likely to have an important function in the central nervous system. RNA blot analysis reveals the relative intensity of testican in various regions of the human brain. Levels of testican message are most pronounced in the thalamus, hippocampus, occipital lobe, nucleus accumbens, temporal lobe, and caudate nucleus, with somewhat lower levels in the cerebral cortex, medulla oblongata, frontal lobe, amygdala, putamen, spinal cord, substantia nigra, and cerebellum. In situ hybridization reveals the cellular distribution of the mRNA within these areas to be highest in neurons and in choroid plexus epithelium, and moderately lower in ependymal cells lining the ventricles and in vascular endothelial cells. Testican mRNA is not detected in oligodendrocytes or in most astrocytes. However, astrocytes in regions of reactive gliosis do express testican mRNA. These findings, along with a cysteine-rich pattern similarity to neurocan, brevican, versican, and other proteoglycans found in brain, suggest that testican may be a part of the specialized extracellular matrix of the brain.

Basal Ganglia↗
PubMed2005

Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex.

Stroke induces axonal sprouting in peri-infarct cortex. A set of growth-associated genes important in axonal sprouting in peripheral nervous system regeneration and cortical development has recently been defined. The expression profiles of these growth-associated genes were defined during the post-stroke axonal sprouting response using a model of stroke in barrel field cortex. Stroke induces sequential waves of neuronal growth-promoting genes during the sprouting response: an early expression peak (SPRR1), a mid expression peak (p21, Ta1 tubulin, L1, MARCKS), a late peak (SCG10, SCLIP), and an early/sustained pattern (GAP43, CAP23, c-jun). These expression peaks correspond to specific time points in the sprouting response. The expression of the growth-inhibiting chondroitin sulfate proteoglycans aggrecan, brevican, versican, and phosphacan are induced late in the sprouting process; except neurocan, which is increased during the peak of the growth-promoting gene expression. The developmentally associated growth inhibitors ephrin-A5, ephB1, semaphorin IIIa, and neuropilin 1 are also induced in the early phases of the sprouting response. At the cellular level, chondroitin sulfate proteoglycans, in the form of peri-neuronal nets, are reduced in the region of axonal sprouting, during the peak of growth-promoting gene expression. These results identify a unique profile of growth-promoting gene expression in adult cortex after stroke, the inhibitory molecules that are present during the sprouting response, and a region in which growth-promoting genes are increased, growth-inhibitory proteins are diminished and axonal sprouting occurs. This region may be a growth-promoting zone after stroke.

Aggrecans↗
PubMed2005

Differential expression of ADAMTS-1, -4, -5 and TIMP-3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of inflammatory demyelination, a pathological event common to multiple sclerosis (MS). During CNS inflammation there are alterations in the extracellular matrix (ECM). A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS)-1, -4 and -5 are proteases present in the CNS, which are able to cleave the aggregating chondroitin sulphate proteoglycans, aggrecan, phosphacan, neurocan and brevican. It is therefore important to investigate changes in their expression in different stages of EAE induction. We have investigated expression of ADAMTS-1, -4, -5 and tissue inhibitor of metalloproteinase (TIMP)-3, by real-time RT-PCR. We have also examined protein expression of ADAMTS-1, -4 and -5 by western blotting and immunocytochemistry in spinal cord from animals at different stages of disease progression. Our study demonstrated a decrease in ADAMTS-4 mRNA and protein expression. TIMP-3 was decreased at the mRNA level although protein levels were increased in diseased animals compared to controls. Our study identifies changes in ADAMTS expression during the course of CNS inflammation which may contribute to ECM degradation and disease progression.

ADAM Proteins↗
PubMed2005

Construction of perineuronal net-like structure by cortical neurons in culture.

Perineuronal nets consisting of chondroitin sulfate proteoglycans and hyaluronic acid are associated with distinct neuronal populations in mammalian brain. Whether neurons or glia cells produce these surface-associated chondroitin sulfate proteoglycan perineuronal nets has remained in question. In the present study, we observed perineuronal net-like structure by rat cortical neurons in dissociated culture using Wisteria floribunda aggulutinin, hyaluronic acid binding protein, and the antibodies recognizing chondroitin sulfate proteoglycans. The double labeling experiments showed that perineuronal net-like structure labeled with Wisteria floribunda aggulutinin was observed often at parvalbumin-positive neurons in dissociated cortical culture without glia. Perineuronal net-like structure was not seen at the early stage of culture, but they became visible concomitantly with neuronal maturation after longer culture. High magnification observation further demonstrated that Wisteria floribunda aggulutinin labeling on cortical neurons was seen as numerous puncta along surface of somata and proximal dendrites, but not axons and synapses. Perineuronal net-like structure on cultured neurons was also visualized using chondroitin sulfate proteoglycan-specific antibodies and hyaluronic acid binding protein. Double labeling study demonstrated that perineuronal net-like structure in cultured cortical neurons was composed of chondroitin sulfate proteoglycans such as neurocan and phosphacan. The hyaluronidase treatment of live neurons abolished cellular labeling of hyaluronic acid binding protein and concomitantly diminished that of Wisteria floribunda aggulutinin. These results indicate that cultured cortical neurons are able to construct perineuronal net-like structure without glial cells.

Animals↗
PubMed2006

Erythropoietin-mediated preservation of the white matter in rat spinal cord injury.

We investigated the effect of a single administration of recombinant human erythropoietin (rhEPO) on the preservation of the ventral white matter of rats at 4 weeks after contusive spinal cord injury (SCI), a time at which functional recovery is significantly improved in comparison to the controls [Gorio A, Necati Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Enver Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99:9450-9455; Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102:16379-16384]. Specifically, we examined, by morphological and cytochemical methods combined with light, confocal and electron microscopy, i) myelin preservation, ii) activation of adult oligodendrocyte progenitors (OPCs) identified for the expression of NG2 transmembrane proteoglycan, iii) changes in the amount of the chondroitin sulfate proteoglycans neurocan, versican and phosphacan and of their glycosaminoglycan component labeled with Wisteria floribunda lectin, and iv) ventral horn density of the serotonergic plexus as a marker of descending motor control axons. Injured rats received either saline or a single dose of rhEPO within 30 min after SCI. The results showed that the significant improvement of functional outcome observed in rhEPO-treated rats was associated with a better preservation of myelin in the ventral white matter. Moreover, the significant increase of both the number of NG2-positive OPCs and the labeling for Nogo-A, a marker of differentiated oligodendrocytes, suggested that rhEPO treatment could result in the generation of new myelinating oligodendrocytes. Sparing of fiber tracts in the ventral white matter was confirmed by the increased density of the serotonergic plexus around motor neurons. As for chondroitin sulfate proteoglycans, only phosphacan, increased in saline-treated rats, returned to normal levels in rhEPO group, probably reflecting a better maintenance of glial-axolemmal relationships along nerve fibers. In conclusion, this investigation expands previous studies supporting the pleiotropic neuroprotective effect of rhEPO on secondary degenerative response and its therapeutic potential for the treatment of SCI and confirms that the preservation of the ventral white matter, which contains descending motor pathways, may be critical for limiting functional deficit.

Animals↗
PubMed1998

Induction of arthritis in BALB/c mice by cartilage link protein: involvement of distinct regions recognized by T and B lymphocytes.

Both type II collagen and the proteoglycan aggrecan are capable of inducing an erosive inflammatory polyarthritis in mice. In this study we provide the first demonstration that link protein (LP), purified from bovine cartilage, can produce a persistent, erosive, inflammatory polyarthritis when injected repeatedly intraperitoneally into BALB/c mice. We discovered a single T-cell epitope, located within residues 266 to 290 of bovine LP (NDGAQIAKVGQIFAAWKLLGYDRCD), which is recognized by bovine LP-specific T lymphocytes. We also identified three immunogenic regions in bovine LP that contain epitopes recognized by antibodies in hyperimmunized sera. One of these B-cell regions is found in the most species-variable domain of LP (residues 1 to 36), whereas the other epitopes are located in the most conserved regions (residues 186 to 230 and 286 to 310). The latter two regions contain an AGWLSDGSVQYP motif shared by the G1 globulin domain of aggrecan core protein, versican, neurocan, glial hyaluronan-binding protein, and the hyaluronan receptor CD44. Our data reveal that the induction of arthritis is associated with antibody reactivities to B-cell epitopes located at residues 1 to 19. Together, these observations show that another cartilage protein, LP, like type II collagen and the proteoglycan aggrecan, is capable of inducing an erosive inflammatory arthritis in mice and that the immunity to LP involves recognition of both T- and B-cell epitopes. This immunity may be of importance in the pathogenesis of inflammatory joint diseases, such as juvenile rheumatoid arthritis, in which cellular immunity to LP has been demonstrated.

Amino Acid Sequence↗
PubMed1998

Developmental regulation of decorin expression in postnatal rat brain.

Here, we report on the expression of the small chondroitin/dermatan sulfate proteoglycan decorin in the developing postnatal rat brain. Northern analysis of brain RNA demonstrated decorin transcripts with peak expression on postnatal day 3 followed by a slow decline to the lower adult level. In situ hybridization and immunohistochemistry revealed postnatal decorin expression in the grey matter of neocortex, hippocampus and thalamus, in myelinated fibre tracts and in several mesenchymal tissues (blood vessels, pia mater and the choroid plexus). In the neocortex, decorin is expressed in a specific laminar pattern with intense staining of the cortical plate and its derivatives, which differs remarkably from the distributions observed for other proteoglycans [B. Miller, A.M. Sheppard, A.R. Bicknese, A.L. Pearlman, Chondroitin sulfate proteoglycans in the developing cerebral cortex: the distribution of neurocan distinguishes forming afferent and efferent axonal pathways, J. Comp. Neurol. 355 (1995) 615-28]. Thus, decorin seems to serve yet unknown functions in the developing rat brain parenchyma in addition to its well-established role as a constituent of the mesenchymal extracellular matrix.

Animals↗
PubMed1999

Domain organization, genomic structure, evolution, and regulation of expression of the aggrecan gene family.

Proteoglycans are complex macromolecules, consisting of a polypeptide backbone to which are covalently attached one or more glycosaminoglycan chains. Molecular cloning has allowed identification of the genes encoding the core proteins of various proteoglycans, leading to a better understanding of the diversity of proteoglycan structure and function, as well as to the evolution of a classification of proteoglycans on the basis of emerging gene families that encode the different core proteins. One such family includes several proteoglycans that have been grouped with aggrecan, the large aggregating chondroitin sulfate proteoglycan of cartilage, based on a high number of sequence similarities within the N- and C-terminal domains. Thus far these proteoglycans include versican, neurocan, and brevican. It is now apparent that these proteins, as a group, are truly a gene family with shared structural motifs on the protein and nucleotide (mRNA) levels, and with nearly identical genomic organizations. Clearly a common ancestral origin is indicated for the members of the aggrecan family of proteoglycans. However, differing patterns of amplification and divergence have also occurred within certain exons across species and family members, leading to the class-characteristic protein motifs in the central carbohydrate-rich region exclusively. Thus the overall domain organization strongly suggests that sequence conservation in the terminal globular domains underlies common functions, whereas differences in the central portions of the genes account for functional specialization among the members of this gene family.

Aggrecans↗
PubMed1999

The glial scar and central nervous system repair.

Damage to the central nervous system (CNS) results in a glial reaction, leading eventually to the formation of a glial scar. In this environment, axon regeneration fails, and remyelination may also be unsuccessful. The glial reaction to injury recruits microglia, oligodendrocyte precursors, meningeal cells, astrocytes and stem cells. Damaged CNS also contains oligodendrocytes and myelin debris. Most of these cell types produce molecules that have been shown to be inhibitory to axon regeneration. Oligodendrocytes produce NI250, myelin-associated glycoprotein (MAG), and tenascin-R, oligodendrocyte precursors produce NG2 DSD-1/phosphacan and versican, astrocytes produce tenascin, brevican, and neurocan, and can be stimulated to produce NG2, meningeal cells produce NG2 and other proteoglycans, and activated microglia produce free radicals, nitric oxide, and arachidonic acid derivatives. Many of these molecules must participate in rendering the damaged CNS inhibitory for axon regeneration. Demyelinated plaques in multiple sclerosis consists mostly of scar-type astrocytes and naked axons. The extent to which the astrocytosis is responsible for blocking remyelination is not established, but astrocytes inhibit the migration of both oligodendrocyte precursors and Schwann cells which must restrict their access to demyelinated axons.

Animals↗
PubMed2000

Synthesis of hyaluronan of distinctly different chain length is regulated by differential expression of Xhas1 and 2 during early development of Xenopus laevis.

The localization of hyaluronan has been determined in tailbud stage embryos of Xenopus laevis using a neurocan-alkaline phosphatase fusion protein. This polysaccharide was located between the germ layers and enriched in mesenchyme, the lumen of the neural tube, the embryonic gut, the hepatic cavity and the heart. A full-length cDNA for a hyaluronan synthase, Xhas2 has been cloned. The expression pattern of Xhas1 and 2 is closely similar to the distribution of hyaluronan in the embryo. Xhas1 produces hyaluronan with a molecular mass of around 40-200 kDa, while the product formed by Xhas2 has a molecular mass above 1 million Da.

Animals↗
PubMed2003

Testican-1 inhibits attachment of Neuro-2a cells.

Testican-1 is a highly conserved, multidomain, chondroitin sulfate proteoglycan that is most abundantly transcribed in the brain by neurons. This testican messenger RNA is not detected in normal quiescent astrocytes, but is up regulated when these cells are activated in response to injury such as cerebral stroke. Other chondroitin sulfate proteoglycans found in glial scars, including neurocan, have been shown to inhibit neural cell attachment and neurite extensions and may thus impede axonal regeneration. Here we report the expression and purification of a proteoglycan form of recombinant testican and its effects on neuron-derived cells in culture. We demonstrate that testican inhibits attachment of Neuro-2a cells and their ability to form neurite extensions. Both testican proteoglycan and the core glycoprotein that has been depleted of chondroitin sulfate inhibit cell attachment. Pre-treatment of the culture substratum with testican inhibits Neuro-2a attachment, but pre-treatment of the cells with testican does not inhibit their attachment. Testican, therefore, blocks attachment sites on cultureware and may also block attachment sites in the extracellular matrix of the brain.

Cell Adhesion↗