Nerve growth factor (NGF) is the best characterized of the peptide growth factors acting on the nervous system, and is now recognized as a member of a family of growth factors, the neurotrophins, that supports a wide variety of neural cells. Initial studies on NGF demonstrated that it was required for the survival and differentiation of sympathetic and sensory neurons. It is now known, in addition, 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, a number of tumor cells, and cells of the immune system, as well. 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 surface of the cell. The binding of NGF to its physiologically-responsive, tyrosine kinase receptor, now known to be the protein product of the trk proto- 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 effects on the cells. These biochemical changes have been studied, in large measure, in PC12, 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 it stops dividing, elaborates neurites, becomes excitable and, to all intents and purposes, goes from a rapidly dividing chromaffin cell to a terminally differentiated sympathetic neuron in a matter of 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. Using this system it has been established that the actions of NGF are mediated, at least in part, by changes in the phosphorylation of key proteins in various compartments of the cell, including the nucleus. It is further known that 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. The ability of NGF to regulate cellular calcium may also be involved in the neuroprotective actions of the neurotrophins, since high levels of calcium produced by ischemia or hypoglycemia may contribute to the death of neurons after these cerebral insults. 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.
