The cell-surface glycoprotein, Cog, has been implicated in hematopoietic and Schwann cell signaling in vitro. In vivo, Schwann cell CD9 expression follows a developmental time course that parallels that of myelin genes. Here we report that Schwann cell CD9 mRNA expression is regulated by axonal contact in culture and in vivo. Following adult rat sciatic nerve injury, Cog mRNA expression in distal nerve sections is correlated with the presence of axons; CD9 is down-regulated when axons are degenerating and is reexpressed when axons are regenerating, but not if they are prevented from doing so by transection. CD9 regulation in cultured Schwann cells is also dependent on the presence of neurons such that dissociated Schwann cells down-regulate CD9 mRNA expression in culture, but in the presence of sensory neurons they continue to express Cog. Therefore, regulation of Schwann cell CD9 expression parallels that of myelin genes protein 0 and myelin basic protein in culture and in vivo. A signaling role for Cog in nerve development and regeneration is proposed.