Nerve growth factor (NGF) is a polypeptide required for the survival, development, and differentiation of sympathetic and sensory neurons. It is also trophic for certain neurons in the central nervous system and has effects on the chromaffin cells of the adrenal medulla, a number of tumor cell lines, and on selective populations of cells in the immune system. The binding of NGF to specific receptors on the surface of its target cells initiates a series of intracellular actions that, among other things, leads to changes in the expression of specific genes. It is the summation of these intracellular actions and gene expressions that comprise the developmental instructions that NGF imparts to responsive cells. These instructions have been studied on a biochemical level, largely through the use of the NGF-responsive tumor cell line, PCI2. This cell, when treated with NGF, stops dividing, elaborates neurites, becomes electrically excitable, and will synapse with appropriate muscle cells in culture. Using the PCI2 cell system, work in this and other laboratories has shown that nerve growth factor treatment leads to the generation of a number of second messengers and alterations in the phosphorylation of specific proteins in virtually every compartment of the cell. This work has led to the general concept that NGF activates a number of parallel phosphorylative cascades in the cell, leading to changes in the phosphorylation and, consequently, the activity of key cellular proteins, including some in the nucleus. The changes seen in the nucleus could alter the properties of the proteins that regulate the expression of the specific genes required for the actions of NGF. It is reasonable to expect that such detailed information about the actions of NGF will shed light on the process of neuronal differentiation and on how such a process malfunctions in specific disease states.
