We examined the effects of nerve growth factor (NGF) and cell-cell contact on expression of the neural cell adhesion molecule L1 in PC12 cells. After 7 d exposure to NGF, but not after exposure to EGF, FGF, TGF beta, or dibutyryl cAMP (dbcAMP), L1 mRNA levels increased fourfold. This increase was not blocked by K252a, an inhibitor of the high-affinity NGF receptor, although neurite extension was completely inhibited. L1 mRNA levels also increased in NGF-treated mutant PC12 cells (PC12nnr5) that lack the high-affinity NGF receptor. The effect of NGF on L1 mRNA was greatest in cells cultured at high density, but its effect on cells cultured at low density was augmented by antibody to L1 (to mimic L1 homophilic binding). Various extracellular matrix components had no differential effects on L1 mRNA levels in either the presence or absence of NGF. Together, these findings suggest that NGF regulates L1 expression by a mechanism that is independent of the high- affinity NGF receptor and that this regulation is modulated by cell- cell contact but not by cell-extracellular matrix interactions.