Chondroitin Sulfate E Regulates Neuronal Adhesion by Promoting Actin Polymerization Through Activation of the VEGF Receptor/Akt/GSK3β Pathway.

Neuronal adhesion is regulated by interactions between neurons and the extracellular matrix and plays a critical role in neural development. Chondroitin sulfate proteoglycans (CSPGs), key structural components of the extracellular matrix in the nervous system, are involved in various processes including neuronal migration, neurite outgrowth, and axonal regeneration. The diverse functions of CSPGs are controlled by the sulfated structures of chondroitin sulfate (CS) polysaccharides. In this study, we found that CS-E, a highly sulfated CS polysaccharide, but not CS-A, CS-B, CS-C, or CS -D, induced the formation of neuronal aggregates in primary cortical cells with features of immature neurons. This effect is likely due to the unique properties of CS-E, which altered cell adhesion to the coated surface of culture coverslips, leading to cell detachment and subsequent aggregate formation. Pharmacological and phosphorylation analyses aimed at elucidating signaling cascades revealed that the VEGF receptor is a cell surface target of CS-E, and subsequent activation of the Akt/GSK3β pathway plays a crucial role in aggregate formation. The c-Raf/GSK3β pathway is also involved in CS-E-induced aggregate formation. Furthermore, actin polymerization and the organization of the F-actin cytoskeleton, which are mediated through activation of the Akt/GSK3β pathway, were required for CS-E-induced aggregate formation. In summary, CS-E regulates neuronal adhesion by activating the VEGF receptor/Akt/GSK3β pathway. The identification of signaling cascades involving CS-E may provide insights into the mechanisms underlying neuronal development.