The chondroitin sulfate proteoglycan versican is one of the major extracellular components in the developing and adultbrain. Here, we show that isoforms of versican play different roles in neuronal differentiation and neurite outgrowth.Expression of versican V1 isoform in PC12 cells induced complete differentiation, whereas expression of V2 induced anaborted differentiation accompanied by apoptosis. V1 promoted neurite outgrowth of hippocampal neurons, but V2 failedto do so. V1 transfection enhanced expression of epidermal growth factor receptor and integrins, and facilitated sustainedextracellular signal-regulated kinase/MAPK phosphorylation. Blockade of the epidermal growth factor receptor, _1integrin, or Src significantly inhibited neuronal differentiation. Finally, we demonstrated that versican V1 isoform alsopromoted differentiation of neural stem cells into neurons. Our results have implications for understanding how versicanregulates neuronal development, function, and repair.