Functions of Chondroitin Sulfate and Heparan Sulfate in the Developing Brain

Abstract

Chondroitin sulfate and heparan sulfate proteoglycans are major components of the cell surface and extracellular matrix in the brain. Both chondroitin sulfate and heparan sulfate are unbranched highly sulfated polysaccharides composed of repeating disaccharide units of glucuronic acid and N-acetylgalactosamine, and glucuronic acid and N-acetylglucosamine, respectively. During their biosynthesis in the Golgi apparatus, these glycosaminoglycans are highly modified by sulfation and C5 epimerization of glucuronic acid, leading to diverse heterogeneity in structure. Their structures are strictly regulated in a cell type-specific manner during development partly by the expression control of various glycosaminoglycan-modifying enzymes. It has been considered that specific combinations of glycosaminoglycan-modifying enzymes generate specific functional microdomains in the glycosaminoglycan chains, which bind selectively with various growth factors, morphogens, axon guidance molecules and extracellular matrix proteins. Recent studies have begun to reveal that the molecular interactions mediated by such glycosaminoglycan microdomains play critical roles in the various signaling pathways essential for the development of the brain.

Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses

“…This is due to normal expression of the other EXT protein, which still has glycosyltransferase activity although significantly less than the amount generated by the EXT1and EXT2 complex as the enzymes cannot substitute for one another during co-polymerisation 9 38–40. Therefore, while residual levels of heparan sulfate facilitate some cellular functions, they are not sufficient for proper neural development including brain morphology and midline axon guidance—processes defective in Ext-mutants 17 18. Collectively, these studies have demonstrated the importance of sufficient and spatiotemporal expression of heparan sulfate biosynthesis enzymes in the development of brain size and structure.…”

Heparan Sulfate and Heparin Promote Faithful Prion Replication in Vitro by Binding to Normal and Abnormal Prion Proteins in Protein Misfolding Cyclic Amplification

“…GAGs, like nucleic acids, are polyanions, and GAGs function in brain development and are critical determinants of brain structure and function (27)(28)(29)(30). The GAG heparan sulfate (HS) localizes at amyloid plaques in the brains of humans and animals with prion disease (31) and Alzheimer's disease (32), and HS is suggested to be involved in the pathogenesis of amyloidosis.…”

Matrix regulators in neural stem cell functions

“…Indeed, HSPGs stabilize the FGF ligand-receptor complex to promote FGF2 signaling [27, 35, 45, 67, 98, 122]. Proteoglycans can also regulate cell adhesion and cell migration through interactions with membrane proteins and other components of the ECM, including integrins, laminin, collagen, and fibronectin [70, 82]. In addition, proteoglycan intracellular functions are likely to contribute to NSPC regulation as they link extracellular signals with cytoskeletal organization and intracellular signaling [12, 33, 48, 81].…”