Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.4 (chondroitinase)
2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chondroitin sulfate proteoglycans (CSPGs) have been implicated as both positive and negative modulators of axonal growth; however, the functional properties of only a few specific CSPGs have been investigated. Here we demonstrate that NG2, an integral membrane CSPG expressed on the surfaces of glial progenitor cells, inhibits neurite growth from neonatal rat cerebellar granule neurons when presented to the cells as a component of the substrate. Growth inhibition occurred when NG2 was mixed with either laminin or L1, two potent promoters of axonal extension. Moreover, when given a choice between surfaces coated with NG2 and laminin or L1, the axons of the cerebellar neurons extended preferentially on laminin or L1 and avoided areas of the substrate containing NG2. The NG2 proteoglycan inhibited neurite growth after digestion with chondroitinase ABC, demonstrating that the inhibitory activity is a property of the core protein and not the covalently attached chondroitin sulfate glycosaminoglycan chains. NG2 also inhibited neurite growth from embryonic rat dorsal root ganglia neurons on substrates containing laminin. However, when the sensory neurons were plated onto surfaces containing the L1 glycoprotein and NG2, neurite growth was not inhibited. These results demonstrate that the NG2 proteoglycan provides an unfavorable substrate for axonal growth. Cells that express this proteoglycan in vivo may participate in axonal guidance by defining areas of the developing CNS that are nonpermissive for axonal extension from specific classes of developing neurons.
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PMID:Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. 799

Anionic sites in the rat sciatic nerve were studied by light and electron microscopy using a fine-granular cationic colloidal iron staining method (Murakami et al., 1986). The axon, as well as the endoneurium, the epineurium and the basement membrane of Schwann cells, were all confirmed to react strongly to the cationic colloidal iron even at a pH value of 1.0-2.0. Prior hyaluronidase digestion decreased the colloidal strain of the epineurium; chondroitinase ABC weakened that of the endoneurium and the basement membrane of Schwann cells. However, as axons retained stainability with cationic colloidal iron even after combined digestion with hyaluronidase, chondroitinase ABC, heparitinase and keratanase, the authors consider sulfated glycoconjugates and not those substances which are digestible with such common enzymes. The acid groups ionized at pH 1.0 are most likely sulfate groups. Methylation deprived the axon of the reactivity to cationic colloidal iron staining, and even subsequent saponification could not recover this reactivity to its full extent. In the axon, electron microscopy revealed a deposition of colloidal iron on the external surfaces of microtubules and neurofilaments in the axoplasm and of very fine filaments connecting them. This highly negatively charged intra-axonal network could also serve toward a supportive function in maintaining the spatial distribution of microtubules either mechanically or through electrostatic repulsion or, possibly, serve as an intra-axona cation exchange reservoir.
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PMID:Strongly anionic sites in peripheral axons of the rat sciatic nerve: light and electron microscopic detection using cationic colloidal iron. 856 39

The glycosaminoglycans of sciatic nerves recovering from crush-injury were studied in adult guinea pigs and compared with those of non-injured mature neural tissues. The glycosaminoglycans were recovered from the 1,900 g supernatant and pellet of the tissue homogenates and assayed for hexuronate contents and susceptibilities to hyaluronidase, chondroitinase ABC, and nitrous acid. In the normal brain and central nerve tracts, the glycosaminoglycans were distributed both in the supernatant and pellet fractions; the brain showed a predominance of chondroitin sulphates but the tracts showed a predominance of heparan sulphates. Twice as much glycosaminoglycans were found in normal sciatic nerves, only in the pellet fraction and with heparan sulphate predominant. In the 2 weeks post-crush, progressive increase in hexuronate was observed, due mainly to additional chondroitin sulphate forms in the supernatant; the pellet fraction in the same period was however similar to the untreated controls in relative abundance of glycosaminoglycan classes and hexuronate content. At 4 weeks post-crush, although the total hexuronate returned to the control level, a significant proportion of glycosaminoglycans remained in the supernatant fraction. Evidence is thus provided for the need to modulate the glycosaminoglycan expression pattern in adult neural tissue to allow post-traumatic tissue remodelling and axonal regrowth.
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PMID:Changes in glycosaminoglycans during regeneration of post-crush sciatic nerves of adult guinea pigs. 895 Jul 6

Proteoglycans influence axonal outgrowth in several experimental paradigms, and their distribution during development suggests a role in axon guidance. We have used a monoclonal antibody, 5D4, that recognizes an epitope on sulfated keratans (KS), to define the distribution of keratan sulfate proteoglycans (KSPGs) in the developing thalamus and cortex of the rat. During development, 5D4 immunolabeling is present on thalamic axons as they grow through the internal capsule and subplate but is not present in the adjacent pathway for cortical efferent axons. Individual thalamic nuclei differ markedly in their expression of KSPGs; these distinctions persist throughout the period of developmentally regulated expression. Major cortical domains also differ in their expression of KSPGs, which are expressed throughout medial (cingulate and retrosplenial) cortex well before neocortex. Immunolabeling for KSPGs diminishes 2 weeks after birth; in the adult it is associated with small glia. The 5D4 epitope is present on several KSPGs (320, 220, and 160 kD) on Western blots during development but only in a broad 200-kD band in adult brain. Immunolabeling is degraded on sections and Western blots by keratanase II but not by keratanase I or chondroitinase ABC, confirming that the antibody recognizes KS. Bands identified by 5D4 on Western blots differ from those identified by antibodies to known KSPGs (aggrecan, claustrin, SV2, ABAKAN, phosphacan-KS), indicating that 5D4 is labeling KSPGs not previously described in the brain. The selective expression of KSPGs during development suggests that they may be a part of the molecular identity of thalamic nuclei and cortical domains that defines their connectivity.
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PMID:Developmental expression of keratan sulfate-like immunoreactivity distinguishes thalamic nuclei and cortical domains. 908 31

Numerous findings support the possibility that highly sulfated proteoglycans are inhibitory molecules which, at high concentration relative to growth-promoting signals, may regulate or guide axonal growth. Although most studies implicate sulfated proteoglycans in the poor regenerative capacity of the central nervous system, inhibitory proteoglycans also may play an important role in the successful regeneration of axons within peripheral nerve. Cultured rat schwannoma and Schwann cells produce chondroitin sulfate proteoglycan (CSPG) which binds to and inhibits the neurite-promoting activity of laminin [Muir et al. (1989) J. Cell Biol. 109:2353]. In the present study, we found a similar neurite-inhibiting activity associated with CSPG isolated from normal adult rat sciatic nerve. Following nerve crush injury, this inhibitory activity was increased sevenfold in regenerating nerve distal to the injury. This increase was largely attenuated by in vivo administration of the proteoglycan synthesis inhibitor beta-D-xyloside. In normal adult nerve, immunolabeling for CSPG core protein was concentrated in slender bands surrounding axon-Schwann cell units and within nodes of Ranvier. Following nerve crush injury, immunolabeling of CSPG and laminin became more intense in distal nerve and CSPG increased within endoneurium and surrounding nerve sheaths. Embryonic dorsal root ganglionic neurons cultured on longitudinal nerve sections extended neurites along the exposed surfaces of Schwann cell basal lamina. The length of neurites was increased 58% on normal nerve sections pretreated with chondroitinase. Even though laminin levels were elevated in basal lamina of injured nerve, neuritic growth on sections of injured nerve was not significant increased unless sections were pretreated with chondroitinase. These results indicate that inhibitory CSPG is up-regulated in injured nerve and plays a role in regulating axonal regeneration.
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PMID:Chondroitin sulfate proteoglycan with neurite-inhibiting activity is up-regulated following peripheral nerve injury. 946 17

We have isolated and characterized the proteoglycan isoforms of versican from bovine brain extracts. Our approach included (i) cDNA cloning and sequencing of the entire open reading frame encoding the bovine versican splice variants; (ii) preparation of antibodies against bovine versican using recombinant core protein fragments and synthetic peptides; (iii) isolation of versican isoforms by ammonium sulfate precipitation followed by anion exchange and hyaluronan affinity chromatography; and (iv) characterization by SDS-polyacrylamide gel electrophoresis and Coomassie Blue staining or immunoblotting. Our results demonstrate that versican V2 is, together with brevican, a major component of the mature brain extracellular matrix. Versicans V0 and V1 are only present in relatively small amounts. Versican V2 migrates after chondroitinase ABC digestion with an apparent molecular mass of about 400 kDa, whereas it barely enters a 4-15% polyacrylamide gel without the enzyme treatment. The 400-kDa product is recognized by antibodies against the glycosaminoglycan-alpha domain and against synthetic NH2- and COOH-terminal peptides. Our preparations contain no major proteolytic products of versican, e.g. hyaluronectin or glial hyaluronate-binding protein. Having biochemical quantities of versican V2 available will allow us to test its putative modulatory role in neuronal cell adhesion and axonal growth.
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PMID:Versican V2 is a major extracellular matrix component of the mature bovine brain. 962 74

Chondroitin sulfate proteoglycans (CSPGs) are implicated in the regulation of axonal growth. We previously reported that the neurite-promoting activity of laminin is inhibited by association with a Schwann cell-derived CSPG and that endoneurial laminin may be inhibited by this CSPG as well [Zuo J, Hernandez YJ, Muir D (1998) Chondroitin sulfate proteoglycan with neurite-inhibiting activity is upregulated after peripheral nerve injury. J Neurobiol 34:41-54]. Mechanisms regulating axonal growth were studied by using an in vitro bioassay in which regenerating embryonic dorsal root ganglionic neurons (DRGn) were grown on sections of normal adult nerve. DRGn achieved slow neuritic growth on sections of normal nerve, which was reduced significantly by treatment with metalloproteinase inhibitors. Similar results were obtained on a synthetic substratum composed of laminin and inhibitory CSPG. DRGn expressed the matrix metalloproteinase, MMP-2, which was transported to the growth cone. Recombinant MMP-2 inactivated the neurite-inhibiting CSPG without hindering the neurite-promoting potential of laminin. Similarly, neuritic growth by DRGn cultured on normal nerve sections was increased markedly by first treating the nerve sections with MMP-2. The proteolytic deinhibition by MMP-2 was equivalent to and nonadditive with that achieved by chondroitinase, suggesting that both enzymes inactivated inhibitory CSPG. Additionally, the increases in neuritic growth resulting from treating nerve sections with MMP-2 or chondroitinase were blocked by anti-laminin antibodies. From these results we conclude that MMP-2 provides a mechanism for the deinhibition of laminin in the endoneurial basal lamina and may play an important role in the regeneration of peripheral nerve.
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PMID:Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite-inhibiting chondroitin sulfate proteoglycan. 965 Dec 3

The contribution of chondroitin sulfate proteoglycan (CSPG) in the suppression of axonal growth in rat spinal cord has been examined by means of an in vitro bioassay in which regenerating neurons are grown on tissue section substrata. Dissociated embryonic chick dorsal root ganglionic neurons were grown on normal and injured adult spinal cord tissue sections treated with chondroitinases. Neuritic growth on normal spinal cord tissue was meager. However, both the percentage of neurons with neurites and the average neurite length were substantially greater on sections treated with chondroitinase ABC. Enzymes that specifically degraded dermatan sulfate or hyaluronan were ineffective. Neuritic growth was significantly greater on injured (compared to normal) spinal cord and a further dramatic increase resulted from chondroitinase ABC treatment. Neurites grew equally within white and gray matter regions after chondroitinase treatment. Observed increases in neurite outgrowth on chondroitinase-treated tissues were largely inhibited in the presence of function-blocking laminin antibodies. These findings indicate that inhibitory CSPG is widely distributed and predominant in both normal and injured spinal cord tissues. Additionally, inhibitory CSPG is implicated in negating the potential stimulatory effects of laminin that might otherwise support spinal cord regeneration.
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PMID:Degradation of chondroitin sulfate proteoglycan enhances the neurite-promoting potential of spinal cord tissue. 987

During development, most thalamocortical axons extend through the deep layers to terminate in layer 4 of neocortex. To elucidate the molecular mechanisms that underlie the formation of layer-specific thalamocortical projections, axon outgrowth from embryonic rat thalamus onto postnatal neocortical slices which had been fixed chemically was used as an experimental model system. When the thalamic explant was juxtaposed to the lateral edge of fixed cortical slice, thalamic axons extended farther in the deep layers than the upper layers. Correspondingly, thalamic axons entering from the ventricular side extended farther than those from the pial side. In contrast, axons from cortical explants cultured next to fixed cortical slices tended to grow nearly as well in the upper as in the deep layers. Biochemical aspects of lamina-specific thalamic axon growth were studied by applying several enzymatic treatments to the cortical slices prior to culturing. Phosphatidylinositol phospholipase C treatment increased elongation of thalamic axons in the upper layers without influencing growth in the deep layers. Neither chondroitinase, heparitinase, nor neuraminidase treatment influenced the overall projection pattern, although neuraminidase slightly decreased axonal elongation in the deep layers. These findings suggest that glycosylphosphatidylinositol-linked molecules in the cortex may contribute to the laminar specificity of thalamocortical projections by suppressing thalamic axon growth in the upper cortical layers.
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PMID:Characterization of factors regulating lamina-specific growth of thalamocortical axons. 1062 1

During neural development retinal ganglion cell axons migrate over the retinal basal lamina (inner limiting membrane, ILM) in directed growth toward the optic nerve. We found that both growth rate and distribution density of the ganglion cell axons on isolated cell-free ILM was greatly inhibited by pretreatment with heparitinase but not with chondroitinase ABC. The persistence of radioactively labeled proteoglycans added to the culture medium eliminated residual heparitinase as an explanation for the inhibition. A cell binding assay showed that heparitinase acted on the ILM to influence axonal behavior without apparent inhibition of cell adhesion. These results indicated that the neurite outgrowth promoting activity of the ILM depended on the heparan sulfate (HS) side chains of its proteoglycans. Basic fibroblast growth factor (bFGF) stimulated additional neuronal sprouting and neurite elongation on the ILM. This neurotropic activity of bFGF was inhibited by heparitinase pretreatment of the ILM, suggesting that bFGF bound to HS on the ILM. The activity of bFGF was enhanced by exogenous heparin added to the culture medium; although heparin alone failed to stimulate either neurite extension or neuronal cell sprouting. These results demonstrate that HS in the ILM possesses neurotropic activity for axons of the ganglion cells by binding bFGF for presentation to cell-surface receptors and may, therefore, play a significant role in stimulating axonal outgrowth during development.
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PMID:Heparan sulfate in the inner limiting membrane of embryonic chicken retina binds basic fibroblast growth factor to promote axonal outgrowth. 1063 Feb 2


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