Structure and function of oversulfated chondroitin sulfate variants: Unique sulfation patterns and neuroregulatory activities

Oversulfated chondroitin sulfate (CS) variant chains, CSD, CS-E, CS-H and CS-K, all of which are characterized by di- or trisulfated disaccharide units, were originally discovered in tissues of lower marine organisms: shark cartilage, squid cartilage, hagfish notochord and king crab cartilage, respectively. Our studies and others have demonstrated oversulfated structures of CS in various vertebrate tissues including mammalian brains. Our studies in collaboration with A. Faissner have recently demonstrated neurite outgrowth promoting activities towards embryonic rat hippocampal neurons for shark cartilage CS-D and squid cartilage CS-E. We have also demonstrated that cortical neuronal cell adhesion, mediated by heparin (Hep)-binding neuroregulatory factor midkine, is specifically inhibited by squid cartilage CS-E as well as Hep. Furthermore we have shown direct molecular interactions of CS-E with midkine. Recent studies by others have also demonstrated the specific binding of oversulfated CS chains to another Hep-binding growth factor pleiotrophin, which forms a unique gene family with midkine. A systematic structural analysis of various oligosaccharides isolated from the oversulfated CS variants with such intriguing biological activities has revealed various characteristic sulfation profiles. Highly heterogenous sulfated patterns found in these oligosaccharides and the specific molecular interactions of the CS chains with Hep-binding growth factors may indicate the occurrence of analogous structures in higher organisms and are involved in the regulation of various biological processes such as neuronal cell adhesion, migration and neurite outgrowth promotion through specific interactions with the corresponding proteins including some Hep-binding growth factors.