Disease relevance of Vcan

• Here we show that versican G3-containing fragments are present at high levels in human astrocytoma [1].
• Differentiation of EL4 lymphoma cells by tumoral environment is associated with inappropriate expression of the large chondroitin sulfate proteoglycan PG-M and the tumor-associated antigen HTgp-175 [2].
• We show that oligodendrocyte precursor cells do not hypertrophy or increase NG2 levels after these lesions [3].
• V3 versican isoform expression has a dual role in human melanoma tumor growth and metastasis [4].

High impact information on Vcan

• Here, we show that release of glutamate from climbing fiber (CF) axons produces AMPA receptor currents with rapid kinetics in these NG2-immunoreactive glial cells (NG2+ cells) in cerebellar slices [5].
• Paired Purkinje cell-NG2+ cell recordings show that one CF can innervate both cell types [5].
• NG2+ cells may receive up to 70 discrete inputs from one CF and, unlike mature Purkinje cells, are often innervated by multiple CFs [5].
• We demonstrate that early postnatal NG2-expressing (NG2+) progenitor cells located in the SVZ self-renew in vitro and display phenotypic features of transit-amplifier type C-like multipotent cells [6].
• We show that grafted early postnatal NG2+ cells generate hippocampal GABAergic interneurons that propagate action potentials and receive functional glutamatergic synaptic inputs [6].

Biological context of Vcan

• The contiguous genomic DNA segment was found to contain exon 7 of the Cspg2 in a position 3' to the transgene insertion site [7].
• Use of cadherin-6 expression as a marker for neural crest demonstrates a striking correlation between up-regulation of versican expression and absence of migrating neural crest cells, both in the mesenchyme lateral to the neural tube and in the lower branchial arches of Sp2H homozygotes [8].
• We have examined the expression of genes encoding extracellular matrix molecules in Sp2H homozygous embryos and find a marked over-expression of transcripts for the chondroitin sulphate proteoglycan versican in the pathways of neural crest cell migration [8].
• The cells in the early stages of the culture only expressed V0 and V1 forms, having more chondroitin sulfate chains among the four variants of versican/PG-M, and treatment of those cells with chondroitinase ABC suppressed subsequent chondrogenesis [9].
• Here, we characterized cartilage versican during development and growth [10].

Anatomical context of Vcan

• The findings of this study and our previous studies of the hdf insertional mutant mouse have shown that normal expression of the Cspg2 gene is required for the successful development of the endocardial cushion swellings and the embryonic heart segments that give rise to the right ventricle and conus/truncus in the outlet of the looped heart [7].
• Pax3 may serve to negatively regulate versican expression during normal development, thereby guiding neural crest cells into their pathways of migration [8].
• Here we showed several lines of evidence for essential roles of versican/PG-M in chondrogenic condensation using a new chondrocytic cell line, N1511 [9].
• Although its transcription level rapidly diminished during growth, versican remained in the articular cartilage [10].
• Immunostaining showed that versican was mainly localized in the interterritorial zone of the articular surface at 2 weeks in mice, whereas aggrecan was in the pericellular zone of prehypertrophic and hypertrophic cells of the growth plate [10].

Associations of Vcan with chemical compounds

• Heparan sulfate, chondroitin-6-sulfate, versican, perlecan, and syndecan-4, although exhibiting some variation in expression were detected during all phases of the migratory process [11].
• Chondrogenic stimuli (treatment with parathyroid hormone, dexamethasone, 10% serum) induced a marked increase in the transcription and protein synthesis of versican/PG-M [9].
• A heparin-binding growth factor, midkine, binds to a chondroitin sulfate proteoglycan, PG-M/versican [12].
• Survival studies following a single injection of BrdU at P18 revealed a decline in the number of BrdU(+)/NG2(+) cells with a concomitant increase in the number of BrdU(+) oligodendrocytes over time, suggesting that the proliferated NG2(+) cells had differentiated into oligodendrocytes [13].
• In cultured granulosa cells, forskolin and phorbol 12 myristate 13-acetate or FSH + testosterone increased expression of versican [14].

Physical interactions of Vcan

• PG-M/versican isolated from day 13 mouse embryos bound midkine with a Kd of 1.0 nM [12].
• These results demonstrate that versican is essential for matrix assembly involving hyaluronan and that diminished versican deposition increases free hyaluronan fragments that interact with CD44 and increase phosphorylation of ERK1/2, leading to cellular senescence [15].

Co-localisations of Vcan

• Punctate immunoreactivity for fibronectin and laminin was found to be colocalized with NG2 on the surface of NG2 cells [16].

Regulatory relationships of Vcan

• Versican/PG-M regulates chondrogenesis as an extracellular matrix molecule crucial for mesenchymal condensation [9].
• Consistent with this hypothesis, Shh induces the expression of the proteoglycan PG-M/versican in the cranial mesoderm, which has been previously implicated in the regulation of the movement of sensory neural precursors [17].
• Versican is expressed strongly in the trabeculated ventricular myocardium, whereas the compact proliferative zone has lower transcript abundance [18].
• The G3 domain of versican inhibits mesenchymal chondrogenesis via the epidermal growth factor-like motifs [19].
• Using a transgenic mouse, we show that NG2 proteoglycan-positive progenitor cells that express the 2',3'-cyclic nucleotide 3'-phosphodiesterase gene display a multipotent phenotype in vitro and generate electrically excitable neurons, as well as astrocytes and oligodendrocytes [20].

Other interactions of Vcan

• By contrast, lung MK and PG-M/versican were downregulated in these mice at fetal day 16 [21].
• Versican, like other chondroitin sulphate proteoglycans, is non-permissive for migration of neural crest cells in vitro, and we suggest that over-expression of this molecule leads to the arrest of neural crest cell migration in splotch embryos [8].
• Chondroitin sulfate chains of versican digested with chondroitinase ABC contained 71% nonsulfated and 28% 4-sulfated unsaturated disaccharides, whereas those of aggrecan contained 25% nonsulfated and 70% 4-sulfated [10].
• In addition, protein and mRNA levels for versican and decorin were downregulated after 40 weeks of diabetes [22].
• Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes [22].

Analytical, diagnostic and therapeutic context of Vcan

• 5. In situ hybridization studies showed a dramatic decrease in MK and PG-M/versican RNA between days 16.5 and 17.5 in GR(WT) but not in GR(null) mice [21].
• In situ hybridization and immunohistochemistry of versican, aggrecan and link protein, and histochemistry of hyaluronan in the developing mouse limb bud cartilage [23].
• Immunoelectron microscopy revealed that most NG2-positive cells in distal stumps had perineurial or fibroblast-like morphologies, with NG2 being concentrated at the poles of the cells in regions exhibiting microvillus-like protrusions or caveolae [24].
• Genes known to be involved in autoimmune response and arthritis, such as those encoding Galectin-3, Versican, and Socs3, were identified and validated by quantitative TaqMan RT-PCR analysis using independent blood samples [25].

References