Nerve growth factor (NGF) was the first recognized and is now one of the best characterized of the peptide growth factors. It is a member of the neurotrophin family of five homologous peptides that supports a wide variety of neuronal cells. NGF is required for the survival and development of sympathetic and sensory neurons. It also acts on specific populations of neurons in the central nervous system, the cells of the adrenal medulla, and a number of tumors as well. For some time these factors have been identified with long-term actions on target cells, such as survival and differentiation, but in recent years it has become clear that they also participate in very short-term changes, such as synaptic plasticity, the basis of neuronal remodeling and, perhaps, of learning and memory. The action of NGF on these different cells is initiated by its binding to specific receptors. The binding activates at least three different signal transduction pathways. These, in turn, lead to alterations in the phosphorylation and, consequently, the function of key proteins in the cells and to changes in the expression of specific genes. These changes in protein function and gene expression, caused by changes in phosphorylation, are the mechanism by which NGF acts on its target cells. Much of the work leading to this concept has been done with the PC12 pheochromocytoma, a cell line derived from a tumor of the rat adrenal medulla. In the presence of NGF, PC12 cells stop dividing, elaborate neurites, become excitable, and will synapse with appropriate muscle cells in culture. Indeed, they change from a rapidly-dividing chromaffin cell to a terminally-differentiated sympathetic neuron within a few days. The changes in phosphorylation that underlie these striking alterations in phenotype occur in virtually every compartment in the cell. Phosphorylation of NGF-stimulated calcium channels appears to regulate the calcium flux across the cell membranes and, in turn, the intracellular calcium levels, and these levels influence the survival of target neurons and regulate the ability of the neuron to withstand environmental insults such as stroke. The coupled release of neurotransmitters certainly plays a part in neurotrophin-induced synaptic plasticity. NGF-induced phosphorylation of the elements that control protein synthesis, such as eIF-4E, eEF-2, and S6, almost certainly alters the rate and specificity of translation. The NGF-induced phosphorylation of certain transcription factors, such as NGFI-B, determines which genes are expressed at specific developmental states and under specific physiological conditions. Finally, the NGF-induced alterations in gene expression control the fate of the cell through changes in the expression of such proteins as the receptors for mitogens, including those for epidermal growth factor. Clinical interest in these peptide factors is intense because of the role they might play in a range of catastrophic neurodegenerative diseases.
