The purpose of this work is to provide information on the mode of action of nerve growth factor. Nerve growth factor is required for the development and maintenance of the sympathetic and sensory nervous systems and may be a prototype of the more than 30 factors now thought to be involved in the growth and maturation of various cell types. The mechanism of nerve growth factor action is of interest because it should lead to an understanding of the way in which gene expression is regulated in neurons and, in turn, to an understanding of how the developmental course of these neurons is determined. A characterization of the genetic program in these cells may reveal how nerve growth factor induces the synthesis of specific enzymes for the biosynthesis of neurotransmitters or for the morphological changes necessary for the neuron to communicate with other cells through synapse formation. Such information may expand our knowledge of the development and differentiation of the nervous system and of the tumors which arise from it. In order to dissect the mechanism of action of nerve growth factor we have focused on the intracellular events immediately following the addition of nerve growth factor to its target cells. We have used primarily the PC12 cell model. We have described a series of protein phosphorylations that are altered by nerve growth factor treatment. One of these phosphorylative changes can be duplicated in a cell-free system, allowing studies to be done on its detailed biochemical mechanism. These phosphorylative events are accompanied by changes in the structure of the DNA, which may underlie the subsequent changes in transcriptional events. The structural changes are followed by changes in the transcription of various genes. One of these, the decreased synthesis of mitogen receptors, may be the cause of the decreased cell division produced by the addition of nerve growth factor. Ongoing studies are designed to explore these several nerve growth factor-induced changes at the molecular level.