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Soldano Ferrone - One of the best experts on this subject based on the ideXlab platform.
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constitutive and tnfα inducible expression of Chondroitin Sulfate Proteoglycan 4 in glioblastoma and neurospheres implications for car t cell therapy
Science Translational Medicine, 2018Co-Authors: Serena Pellegatta, Soldano Ferrone, Barbara Savoldo, Natalia Di Ianni, Cristina Corbetta, Yuhui Chen, Monica Patane, Chuang Sun, Bianca Pollo, Francesco DimecoAbstract:The heterogeneous expression of tumor-associated antigens limits the efficacy of chimeric antigen receptor (CAR)-redirected T cells (CAR-Ts) for the treatment of glioblastoma (GBM). We have found that Chondroitin Sulfate Proteoglycan 4 (CSPG4) is highly expressed in 67% of the GBM specimens with limited heterogeneity. CSPG4 is also expressed on primary GBM-derived cells, grown in vitro as neurospheres (GBM-NS), which recapitulate the histopathology and molecular characteristics of primary GBM. CSPG4.CAR-Ts efficiently controlled the growth of GBM-NS in vitro and in vivo upon intracranial tumor inoculation. Moreover, CSPG4.CAR-Ts were also effective against GBM-NS with moderate to low expression of CSPG4. This effect was mediated by the in vivo up-regulation of CSPG4 on tumor cells, induced by tumor necrosis factor-α (TNFα) released by the microglia surrounding the tumor. Overall, the constitutive and TNFα-inducible expression of CSPG4 in GBM may greatly reduce the risk of tumor cell escape observed when targeted antigens are heterogeneously expressed on tumor cells.
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Chondroitin Sulfate Proteoglycan 4 as a target for chimeric antigen receptor based t cell immunotherapy of solid tumors
Expert Opinion on Therapeutic Targets, 2015Co-Authors: Yangyang Wang, Soldano Ferrone, Claudia Geldres, Gianpietro DottiAbstract:Introduction: Proteoglycans are critical molecules involved in multiple physiological cell functions, but also key players in cancer development and progression. In particular, Chondroitin Sulfate Proteoglycan 4 (CSPG4) is recognized as an attractive target for antibody-based approaches because of its high expression on cancer cells in several types of human malignancies and its restricted distribution in normal tissues.Areas covered: Adoptive transfer of genetically modified T cells is emerging as a powerful therapeutic approach in cancer patients. In this regard, the selection of the appropriate antigen to be targeted in solid tumors becomes a critical aspect in promoting potent antitumor effects while preventing toxicities. This review summarizes the authors’ current knowledge on the expression and function of CSPG4 in normal tissues and malignant tumors, with a particular focus on the potential use of CSPG4 as a target for antigen-specificity redirected T cells.Expert opinion: T cells expressing a CSP...
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Chondroitin Sulfate Proteoglycan-4 (CSPG4)-Specific Monoclonal Antibody 225.28 in Detection of Acute Myeloid Leukemia Blasts
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, 2015Co-Authors: Moon Fenton, Theresa L. Whiteside, Soldano Ferrone, Michael BoyiadzisAbstract:Chondroitin Sulfate Proteoglycan-4 (CSPG4), a membrane-bound Proteoglycan known to be expressed on the surface of malignant cells, has a restricted distribution in normal tissues. CSPG4 is a potential candidate tumor marker. We investigate CSPG4 expression on blasts in newly diagnosed acute myeloid leukemia (AML) patients and its relation with cytogenetic abnormalities and molecular markers known to have prognostic significance in this disease. Using hybridoma technology, we generated a specific monoclonal antibody (mAb), mAb 225.28, reactive with CSPG4. Blast samples obtained from the peripheral blood of newly diagnosed AML patients were analyzed for CSPG4 expression using the CSPG4-specific mAb and multiparameter flow cytometry. The results were correlated with cytogenetic and molecular characteristics of AML. CSPG4 was found to be expressed on a variable fraction of leukemic blasts in all AML patients with different leukemia morphology, including monoblastic cases. Reactivity of CSPG4-specific mAb with leukemic blasts was not limited to those with the rearranged MLL gene. CSPG4 was also expressed on AML blasts with a complex karyotype, FLT3 mutation, or NPM1 mutation. The results indicate that CSPG4 is expressed and detectable by flow cytometry using the mAb 225.28 on a proportion of blasts of all subtypes of AML irrespective of cytogenetic and molecular abnormalities. mAb 225.28 could be useful in detecting AML blasts by flow cytometry.
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multiple chimeric antigen receptors successfully target Chondroitin Sulfate Proteoglycan 4 in several different cancer histologies and cancer stem cells
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Rachel E Beard, Daniel Abatedaga, Zhili Zheng, Kiran H Lagisetty, William R Burns, Eric Tran, Stephen M Hewitt, Shannon F Rosati, Howard A Fine, Soldano FerroneAbstract:Background The development of immunotherapy has led to significant progress in the treatment of metastatic cancer, including the development of genetic engineering technologies that redirect lymphocytes to recognize and target a wide variety of tumor antigens. Chimeric antigen receptors (CARs) are hybrid proteins combining antibody recognition domains linked to T cell signaling elements. Clinical trials of CAR-transduced peripheral blood lymphocytes (PBL) have induced remission of both solid organ and hematologic malignancies. Chondroitin Sulfate Proteoglycan 4 (CSPG4) is a promising target antigen that is overexpressed in multiple cancer histologies including melanoma, triple-negative breast cancer, glioblastoma, mesothelioma and sarcoma.
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Detection of Chondroitin Sulfate Proteoglycan 4 (CSPG4) in melanoma
Methods in molecular biology (Clifton N.J.), 2013Co-Authors: Yangyang Wang, Francesco Sabbatino, Xinhui Wang, Soldano FerroneAbstract:The tumor antigen Chondroitin Sulfate Proteoglycan 4 (CSPG4) appears to be a useful biomarker to identify melanoma cells and an attractive target to apply antibody-based immunotherapy for the treatment of melanoma. Here we described the reverse transcription-polymerase chain reaction (RT-PCR) method and the immunohistochemical (IHC) staining method to detect the expression of CSPG4 in melanoma cells and tissues.
Atsuhiko Oohira - One of the best experts on this subject based on the ideXlab platform.
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activity dependent regulation of a Chondroitin Sulfate Proteoglycan 6b4 phosphacan rptpβ in the hypothalamic supraoptic nucleus
Brain Research, 2004Co-Authors: Seiji Miyata, Akio Akagi, Noriko Hayashi, Kazutada Watanabe, Atsuhiko OohiraAbstract:The hypothalamic magnocellular neurons, synthesizing arginine vasopressin (AVP) and oxytocin, are well known to show structural plasticity during chronic physiological stimulation. We have previously reported that 6B4 phosphacan/receptor-type protein-tyrosine phosphataseβ (RPTPβ), a Chondroitin Sulfate Proteoglycan is highly expressed in the supraoptic nucleus (SON) of adult hypothalamus. Here, we undertook to study the activity-dependent regulation of 6B4 phosphacan/RPTPβ in this system. Double labeling confocal microscopy demonstrated in the SON that 6B4 phosphacan/RPTPβ-immunoreactive perineuronal nets were seen around AVP-containing somata and dendrites and its distribution pattern was well coincided with that of TAG-1. Quantitative immunohistochemical and Western analyses showed that 1-week salt loading, known as the chronic physiological stimulation for inducing the structural changes such as synaptic remodeling and direct neuronal membrane apposition, decreased 6B4 phosphacan/RPTPβ levels in the SON, but did not alter TAG-1 levels. The 6B4 phosphacan/RPTPβ levels were returned to control basal values within 3 weeks after the cessation of the chronic stimulation. Activity-dependent decreases in 6B4 phosphacan/RPTPβ levels of the SON were confirmed when Western and immunohistochemical samples were digested with Chondroitinase ABC, indicating that the decrease in 6B4 phosphacan/RPTPβ levels was due to disappearance of 6B4 phosphacan/RPTPβ core protein rather than increase in Chondroitin Sulfate glycosaminoglycans. With electron microscopy, the electron-dense immunoproducts for 6B4 phosphacan/RPTPβ were found on the membrane surface of axons and glial processes, but not at synaptic junctions in control SON, and its immunoreactivity was eliminated with the chronic salt loading. The present results indicate that the levels of 6B4 phosphacan/RPTPβ are regulated with activity-dependent manner and may be concerned with the structural plasticity seen in the SON.
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phosphorylation of neuroglycan c a brain specific transmembrane Chondroitin Sulfate Proteoglycan and its localization in the lipid rafts
Journal of Biological Chemistry, 2002Co-Authors: Shinobu Yamauchi, Yoshihito Tokita, Sachiko Aono, Fumiko Matsui, Takuya Shuo, Hidenori Ito, Kanefusa Kato, Kohji Kasahara, Atsuhiko OohiraAbstract:Neuroglycan C (NGC) is a brain-specific transmembrane Chondroitin Sulfate Proteoglycan. In the present study, we examined whether NGC could be phosphorylated in neural cells. On metabolic labeling of cultured cerebral cortical cells from the rat fetus with (32)P(i), serine residues in NGC were radiolabeled. Some NGC became detectable in the raft fraction from the rat cerebrum, a signaling microdomain of the plasma membrane, with cerebral development. NGC from the non-raft fraction, not the raft fraction, could be phosphorylated by an in vitro kinase reaction. The phosphorylation of NGC was inhibited by adding to the reaction mixture a recombinant peptide representing the ectodomain of NGC, but not by adding a peptide representing its cytoplasmic domain. NGC could be labeled by an in vitro kinase reaction using [gamma-(32)P]GTP as well as [gamma-(32)P]ATP, and this kinase activity was partially inhibited by 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole, a selective inhibitor of casein kinase II. In addition to the intracellular phosphorylation, NGC was also phosphorylated at the cell surface by an ectoprotein kinase. This is the first report to demonstrate that NGC can be phosphorylated both intracellularly and pericellularly, and our findings suggest that a kinase with a specificity similar to that of casein kinase II is responsible for the NGC ectodomain phosphorylation.
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purification characterization and developmental expression of a brain specific Chondroitin Sulfate Proteoglycan 6b4 Proteoglycan phosphacan
Neuroscience, 1995Co-Authors: Nobuaki Maeda, Atsuhiko Oohira, H Hamanaka, Masaharu NodaAbstract:Abstract A large brain-specific Chondroitin Sulfate Proteoglycan, identified with monoclonal antibody 6B4 (6B4 Proteoglycan/phosphacan), was isolated from rat brain. Soluble Proteoglycans in the phosphate-buffered saline extract from 20-day-old rat whole brain were fractionated by anion exchange chromatography and CsCl density gradient centrifugation. 6B4 Proteoglycan was further purified by gel filtration and additional ion exchange chromatography. The molecular mass of 6B4 Proteoglycan shifted from 800 to 300 × 10 3 mol. wt after Chondroitinase ABC digestion. The core protein was substituted with Chondroitin Sulfate chains with an average molecular weight of 21, 000, keratan Sulfate and HNK-1 carbohydrates. Glycosidase digestion of 6B4 Proteoglycan with O-glycanase, N-glycanase, endo-β-galactosidase, or keratanase did not remove the HNK-1 epitopes. The expression of 6B4 Proteoglycan was developmentally regulated in the rat cerebral cortex; appearing first at embryonic day 14, peaking at postnatal day 0, and persisting throughout adulthood at a lower level. Immunohistochemical analysis indicated that 6B4 Proteoglycan was distributed along the radial glial fibers and on the migrating neurons in the embryonal rat cerebrum. The radial glial fibers were stained intensely all along their length, but the neurons in the cortical plate were not stained in contrast to the moderate staining of the migrating neurons in the intermediate zone and the subplate. From postnatal day 5 to postnatal day 20, 6B4 Proteoglycan was present throughout the cortex. After postnatal day 30, staining of the neuropil was weakened, and the expression of 6B4 proteoglcyan was restricted around subsets of neurons. The positive neurons were mostly non-pyramidal cells (>95%) and were relatively concentrated in layers IV and VI of the primary somatosensory cortex. Immunohistochemical analysis of the dissociated cortical neurons indicated that 6B4 Proteoglycan was distributed on the cell bodies and neurites. 6B4 Proteoglycan strikingly promoted neurite extension of cortical neurons from embryonic day-16 rat embryos when coated on coverslips as a substrate. 6B4 Proteoglycan is a brain-specific Chondroitin Sulfate Proteoglycan which carries keratan Sulfate and HNK-1 carbohydrates. The spatiotemporal expression profile and effects on the dissociated cerebral neurons suggest that 5B4 Proteoglycan plays important roles in the migration and differentiation of neurons in the immature cortex and also in the maintenance of subsets of neurons in the mature cortex.
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Core Protein of Chondroitin Sulfate Proteoglycan Promotes Neurite Outgrowth from Cultured Neocortical Neurons
Journal of neurochemistry, 1991Co-Authors: Noboru Iijima, Atsuhiko Oohira, Toshio Mori, Katsuaki Kitabatake, Shinichi KohsakaAbstract:Chondroitin Sulfate Proteoglycan (CS-PG) was purified from rat brain and examined for its effect on neurite outgrowth in primary cultures of embryonic rat neocortical neurons. Neurite outgrowth was increased in culture wells coated with CS-PG. The core protein and glycosaminoglycan (GAG) prepared from the CS-PG were also examined for neurite-promoting activity. The activity was observed in culture wells coated with the core protein but not with GAG. These results suggest that CS-PG stimulates neurite outgrowth from the cultured neurons via its core protein.
Richard U. Margolis - One of the best experts on this subject based on the ideXlab platform.
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the core protein of the Chondroitin Sulfate Proteoglycan phosphacan is a high affinity ligand of fibroblast growth factor 2 and potentiates its mitogenic activity
Journal of Biological Chemistry, 1998Co-Authors: Peter Milev, Renée K. Margolis, Hubert Monnerie, Susanna Popp, Richard U. MargolisAbstract: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.
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phosphacan a Chondroitin Sulfate Proteoglycan of brain that interacts with neurons and neural cell adhesion molecules is an extracellular variant of a receptor type protein tyrosine phosphatase
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Patrice Maurel, Uwe Rauch, Renée K. Margolis, Manuela Flad, Richard U. MargolisAbstract:We have identified cDNA clones encoding a Chondroitin Sulfate Proteoglycan of rat brain (previously designated 3F8 and now named phosphacan) that binds to neurons and neural cell-adhesion molecules. A sequence of 1616 amino acids deduced from a 4.8-kb open reading frame contains the N-terminal amino acid sequence of the 3F8 core glycoprotein as well as four internal CNBr, tryptic, and endoproteinase Lys-C peptide sequences from the Proteoglycan. The deduced amino acid sequence, beginning with a 24-amino acid signal peptide, reveals an N-terminal domain of 255 amino acids homologous to carbonic anhydrases. The entire amino acid sequence deduced from our cDNA clones corresponds to the extracellular portion of a human receptor-type protein tyrosine phosphatase (RPTP zeta/beta) with which it has 76% identity, and the Proteoglycan may represent an mRNA splicing variant of the larger transmembrane protein. RNA analysis demonstrated that a probe to the N-terminal carbonic anhydrase domain of the Proteoglycan hybridizes with rat brain mRNA of 9.5, 8.4, and 6.4 kb, whereas probes to the phosphatase domains hybridize with only the 9.5-kb message and with the 6.4-kb message (which corresponds to a previously identified variant of the transmembrane protein in which half of the extracellular domain is deleted). The 30 N-terminal amino acids of the 3H1 Chondroitin/keratan Sulfate Proteoglycan of brain are identical to those of the 3F8 Proteoglycan, and six internal tryptic peptide sequences also matched those found in sequenced peptides of the 3F8 Proteoglycan and/or amino acid sequences deduced from the cDNA clones. We therefore conclude that the 3H1 Chondroitin/keratan Sulfate Proteoglycan and the 3F8 Chondroitin Sulfate Proteoglycan represent glycosylation and possible extracellular splicing variants of a receptor-type protein tyrosine phosphatase. These Proteoglycans may modulate cell interactions and other developmental processes in nervous tissue through heterophilic binding to cell-surface and extracellular matrix molecules, and by competition with ligands of the transmembrane phosphatase.
James B Mccarthy - One of the best experts on this subject based on the ideXlab platform.
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Chondroitin Sulfate Proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain
Melanoma Research, 2019Co-Authors: Jianbo Yang, Matthew Price, Leah Colvin E Wanshura, Danny R Welch, Sean D Conner, Jonathan N Sachs, Eva A Turley, James B MccarthyAbstract:Chondroitin Sulfate Proteoglycan 4 (CSPG4) is a cell surface Proteoglycan that enhances malignant potential in melanoma and several other tumor types. CSPG4 functions as a transmembrane scaffold in melanoma cells to activate oncogenic signaling pathways such as focal adhesion kinase (FAK) and extracellular signal regulated kinases 1,2, that control motility, invasion and anchorage independent growth. Here, we demonstrate that CSPG4 promotes directional motility and anchorage independent growth of melanoma cells by organizing and positioning a signaling complex containing activated FAK to lipid rafts within the plasma membrane of migrating cells. This FAK-containing signal transduction platform, which consists of syntenin-1, active Src and caveolin-1 requires the cytoplasmic domain of CSPG4 for assembly. Enhanced directional motility promoted by this complex also requires a CSPG4 transmembrane cysteine residue C2230. Substituting C2230 with alanine (CSPG4) still permits assembly of the signaling complex, however Src remains in an inactive state. CSPG4 also fails to promote anchorage independent growth and activation of extracellular signal regulated kinases 1,2. Therapies that target the transmembrane domain of CSPG4 could be a novel strategy for limiting progression by disrupting its function as a compartmentalized motogenic and growth-promoting oncogenic signaling node.
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melanoma Chondroitin Sulfate Proteoglycan enhances fak and erk activation by distinct mechanisms
Journal of Cell Biology, 2004Co-Authors: Jianbo Yang, Soldano Ferrone, Matthew Price, Cheryl L Neudauer, Christopher M Wilson, Hong Xia, Joji Iida, Melanie A Simpson, James B MccarthyAbstract:Melanoma Chondroitin Sulfate Proteoglycan (MCSP) is an early cell surface melanoma progression marker implicated in stimulating tumor cell proliferation, migration, and invasion. Focal adhesion kinase (FAK) plays a pivotal role in integrating growth factor and adhesion-related signaling pathways, facilitating cell spreading and migration. Extracellular signal–regulated kinase (ERK) 1 and 2, implicated in tumor growth and survival, has also been linked to clinical melanoma progression. We have cloned the MCSP core protein and expressed it in the MCSP-negative melanoma cell line WM1552C. Expression of MCSP enhances integrin-mediated cell spreading, FAK phosphorylation, and activation of ERK1/2. MCSP transfectants exhibit extensive MCSP-rich microspikes on adherent cells, where it also colocalizes with α4 integrin. Enhanced activation of FAK and ERK1/2 by MCSP appears to involve independent mechanisms because inhibition of FAK activation had no effect on ERK1/2 phosphorylation. These results indicate that MCSP may facilitate primary melanoma progression by enhancing the activation of key signaling pathways important for tumor invasion and growth.
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melanoma Chondroitin Sulfate Proteoglycan regulates matrix metalloproteinase dependent human melanoma invasion into type i collagen
Journal of Biological Chemistry, 2001Co-Authors: Joji Iida, Melanie A Simpson, Duanqing Pei, Tiebang Kang, Meenhard Herlyn, Leo T Furcht, James B MccarthyAbstract:Tumor cell adhesion and proteolysis of the extracellular matrix proteins surrounding the cells are tightly linked processes in tumor invasion. In this study, we sought to identify components of the cell surface of a vertical growth phase melanoma cell line, WM1341D, that mediate invasive cellular behavior. We determined by antisense inhibition that melanoma Chondroitin Sulfate Proteoglycan (MCSP) and membrane-type 3 matrix metalloproteinase (MT3-MMP) expressed on WM1341D are required for invasion of type I collagen and degradation of type I gelatin. MT3-MMP co-immunoprecipitated with MCSP in WM1341D melanoma cells cultured on type I collagen or laminin. The association between MT3-MMP and MCSP was largely disrupted by removing Chondroitin Sulfate glycosaminoglycan (CS) from the cell surface, suggesting CS could mediate the association between the two cell surface core proteins. Recombinant MT3-MMP and MT3-MMP from whole cell lysates of WM1341D cells were specifically eluted from CS- conjugated affinity columns. The results indicate that MT3-MMP possesses the potential to promote melanoma invasion and proteolysis and that the formation of a complex between MT3-MMP and MCSP may be a crucial step in activating these processes.
Masaharu Noda - One of the best experts on this subject based on the ideXlab platform.
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purification characterization and developmental expression of a brain specific Chondroitin Sulfate Proteoglycan 6b4 Proteoglycan phosphacan
Neuroscience, 1995Co-Authors: Nobuaki Maeda, Atsuhiko Oohira, H Hamanaka, Masaharu NodaAbstract:Abstract A large brain-specific Chondroitin Sulfate Proteoglycan, identified with monoclonal antibody 6B4 (6B4 Proteoglycan/phosphacan), was isolated from rat brain. Soluble Proteoglycans in the phosphate-buffered saline extract from 20-day-old rat whole brain were fractionated by anion exchange chromatography and CsCl density gradient centrifugation. 6B4 Proteoglycan was further purified by gel filtration and additional ion exchange chromatography. The molecular mass of 6B4 Proteoglycan shifted from 800 to 300 × 10 3 mol. wt after Chondroitinase ABC digestion. The core protein was substituted with Chondroitin Sulfate chains with an average molecular weight of 21, 000, keratan Sulfate and HNK-1 carbohydrates. Glycosidase digestion of 6B4 Proteoglycan with O-glycanase, N-glycanase, endo-β-galactosidase, or keratanase did not remove the HNK-1 epitopes. The expression of 6B4 Proteoglycan was developmentally regulated in the rat cerebral cortex; appearing first at embryonic day 14, peaking at postnatal day 0, and persisting throughout adulthood at a lower level. Immunohistochemical analysis indicated that 6B4 Proteoglycan was distributed along the radial glial fibers and on the migrating neurons in the embryonal rat cerebrum. The radial glial fibers were stained intensely all along their length, but the neurons in the cortical plate were not stained in contrast to the moderate staining of the migrating neurons in the intermediate zone and the subplate. From postnatal day 5 to postnatal day 20, 6B4 Proteoglycan was present throughout the cortex. After postnatal day 30, staining of the neuropil was weakened, and the expression of 6B4 proteoglcyan was restricted around subsets of neurons. The positive neurons were mostly non-pyramidal cells (>95%) and were relatively concentrated in layers IV and VI of the primary somatosensory cortex. Immunohistochemical analysis of the dissociated cortical neurons indicated that 6B4 Proteoglycan was distributed on the cell bodies and neurites. 6B4 Proteoglycan strikingly promoted neurite extension of cortical neurons from embryonic day-16 rat embryos when coated on coverslips as a substrate. 6B4 Proteoglycan is a brain-specific Chondroitin Sulfate Proteoglycan which carries keratan Sulfate and HNK-1 carbohydrates. The spatiotemporal expression profile and effects on the dissociated cerebral neurons suggest that 5B4 Proteoglycan plays important roles in the migration and differentiation of neurons in the immature cortex and also in the maintenance of subsets of neurons in the mature cortex.