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We have shown that over-sulfated chondroitin sulfate/ dermatan sulfate (CS/DS) chains from various marine organisms exhibit growth factor binding activities and neurite outgrowth-promoting activities in embryonic mouse hippocampal neurons in vitro. In this study we demonstrated that CS/DS hybrid chains purified from embryonic pig brain displayed marked neuritogenic activity and growth factor binding activities toward fibroblast growth factor 2 (FGF2), FGF10, FGF18, pleiotrophin, and midkine, all of which exhibit neuroregulatory activities in the brain. In contrast, the CS/DS preparation from adult pig brain showed considerably less activity to bind these growth factors and no neuritogenic activity. Structural analysis indicated that the average size of the CS/DS chains was similar (40 kDa) between these two preparations, but the disaccharide compositions differed considerably, with a significant proportion of L-iduronic acid (IdoUA)-containing disaccharides (8ϳ9%) in the CS/DS chains from embryos but not in those from adults (<1%). Interestingly, both neurite outgrowth-promoting activity and growth factor binding activities of the CS/DS chains from embryos were abolished by digestion not only with chondroitinase ABC but also with chondroitinase B, suggesting that the IdoUAcontaining motifs are essential for these activities. These findings imply that the temporal expression of CS/DS hybrid structures containing both GlcUA and IdoUA and binding activities toward various growth factors play important roles in neurogenesis in the early stages of the development of the brain. Chondroitin sulfate proteoglycans (CS-PGs)1 are complex macromolecules consisting of a protein core and at least one covalently linked CS glycosaminoglycan (GAG) chain and are ubiquitous components in the extracellular matrices of connective tissues and at the surfaces of many cell types (for reviews, see Refs. 1-3). In the mammalian brain CS-PGs are common extracellular matrix components with a highly regulated spatiotemporal expression (4 -8). Although the CS chains attached to CS-PGs have attracted little attention until recently compared with heparan sulfate (9), recent advances in the structural biology of CS chains have suggested important biological functions in the development of the brain (10). Several studies have demonstrated that the composition of CS chains changes with aging and normal brain maturation and that some CS epitopes are only found in specific sections of the avian and mammalian brain (7,8,11). The developmentally regulated expression and tissue-specific distribution of CS variants suggest that CS chains differing in the degree and profile of sulfation exhibit distinct functions during the development of the brain.The functions of CS-PGs and CS chains in the central nervous system can be categorized as the regulation of cell adhesion and migration, neurite formation, polarization of neurons, synaptic plasticity, survival of neurons, etc. (for reviews, see Ref. 1 and 4). Concerning the neurite formation, studies have sh...