Nerve growth factor (NGF) is one of the longest known and best characterized of the peptide growth factors. The initial studies on NGF demonstrated that it was required for the survival of sympathetic and sensory neurons. It is now known, as well, to influence the development of a wide variety of cell types, including certain neurons in the central nervous system, the chromaffin cells of the adrenal medulla, and a number of tumor cells. The actions of NGF on these different cells are not necessarily the same, but they are all initiated by the binding of the peptide to specific, high-affinity receptors on the cell. The binding of NGF to its physiologically-responsive receptor, now known to be the protein product of the trk oncogene, initiates a number of intracellular actions that lead to alterations in the function of key proteins in the cell and to changes in the expression of specific genes. These changes in protein function and in gene expression are the mechanism by which NGF exerts its developmental effects on the cells. These biochemical changes have been studied, in large part, in PCI2, a cell line derived from a tumor of the rat adrenal medulla. This cell line represents one of the most informative differentiating systems available. In the presence of NGF, PC12 cells stop dividing, elaborate neurites, become excitable and, go from a rapidly dividing chromaffin cell to a terminally differentiated sympathetic neuron in a few days. With this system it is possible to ask questions about how NGF acts, not only at the biochemical level, but also how it produces such global changes in the cell phenotype. It has been established that the actions of NGF are mediated by changes in the phosphorylation of key proteins in various compartments of the cell, including the nucleus. These phosphorylative changes are accompanied by changes in the function of these proteins. One of the functional changes that may be part of the mechanism by which the cell survives is an NGF-induced change in the ability of the cell to take up calcium, since neuronal survival appears to be fostered by increased intracellular calcium. Another functional change that may be part of the mechanism by which the cell is instructed to stop dividing is an NGF-induced decrease in the number of mitogen receptors on the cell surface, since such. receptors regulate the ability of mitogens to promote cell division. It is reasonable to expect that a detailed knowledge of how NGF acts in this system will illuminate the overall mechanism of neuronal differentiation and survival. This, in turn, could provide insights into disease states in which neurons either develop inappropriately or die prematurely.
