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 a number of tumor cell lines. NGF binds to specific receptors on the surface of its target cells, initiates a chain of intracellular events, and, through these intracellular actions, controls the expression of specific genes. It is the summation of these intracellular actions and gene expressions that constitute the developmental instructions NGF imparts to responsive cells. The molecular mechanism(s) by which the factor controls gene expression is not known in fine detail, but, through the work in this and other laboratories, the cascade of intracellular events initiated at the receptor is becoming clarified. Substantial progress has also been made toward an understanding of which genes are required for NGF action and how through the study of the very informative cell line, PC12. When treated with nerve growth factor, PC12 cells stop dividing, elaborate neurites, become electrically excitable, and will synapse with appropriate muscle cells in culture. PC12 has become a premiere tool for the study of nerve growth factor, and has received substantial attention as a model for neuronal differentiation in general. Using the PC12 system, we and others have observed the NGF-induced increase of a number of second messengers. These changes in second messenger levels could be expected to alter the phosphorylation patterns in the cell and, accordingly, we and others have observed a number of such changes. These include increases in the phosphorylation of a nuclear protein called SMP and the ribosomal protein S6, and a decrease in the phosphorylation of the soluble protein, elongation factor 2 (EF-2). Biochemical dissection of these changes in phosphorylation has led to the concept that NGF acts in the cell by activating a number of parallel phosphorylative cascades, all emanating from the receptor, but keyed by different second messenger systems. These cascades carry the NGF signal to various parts of the cell, including the nucleus, where the changes in the phosphorylation of key proteins cause changes in their function. The changes occurring in the nucleus could, then, lead to changes in the expression of specific genes. As yet unknown is the chemistry of the reaction occurring immediately after the combination of NGF with its receptor and linking this signal with the relevant kinases in the cell. It has been suggested that this coupling is accomplished by the combination of the receptor with specific proteins recruited from the soluble portion of the cell. It is reasonable to hope that an understanding of the actions of nerve growth factor will shed light on the process of neuronal differentiation.
