Nerve growth factor (NGF) induced morphological differentiation of the pheochromocytoma PC12 cell line is accompanied by cell surface modulation of the expression of specific cell surface recognition molecules. Changes in the relative expression of the Thy-1 glycoprotein, the neural cell adhesion molecule (N-CAM) and the LI antigen correlate with the onset of neuritic outgrowth indicating a role for these molecules in the neuritogenic process. NGF induced modulation of cell surface glycoprotein expression is, initially brought about by transcription dependent mechanisms, suggesting that the PC12 cell may be a suitable model for the investigation of primary signal transduction events. Studies utilising activators of adenylate cyclase and protein kinase C demonstrate that NGF induced differentiation events are mediated by a variety of independently acting transduction routes. Morphological and biochemical responses to NGF are sensitive to secondary cellular signals. Activators of adenylate cyclase acted synergistically with NGF to promote an accelerated phase of neuritic outgrowth while concomitantly causing differential modulation of NGF induced glycoprotein expression. Analysis of the morphological and biochemical status of PC12 cells grown on monolayer cultures of non-neuronal cells provided further evidence that responses to NGF are not immutable. While growth on myotubes and glioma cells provided permissible substrates for differentiation, PC12 cells grown on monolayers of skin fibroblasts failed to respond morphologically to NGF and in addition, NGF induced increases in the expression of neurofilament protein and the Thy-1 antigen were suppressed. The ability of primed PC12 cells to differentiate on fibroblast monolayers indicates that the inhibitory effects of fibroblast contact are directed at a component of primary, transcription dependent NGF-induced gene activation. Finally, the basic fibroblast growth factor (bFGF) was able to reproduce morphological and biochemical responses associated with NGF induced differentiation. A kinase inhibitor, K252a, was used to discriminate between responses induced by the two growth factors since its effects are specific for NGF
