Nerve growth factor in neuronal development and maintenance

One of the major roles of nerve growth factor (NGF) is to mediate the selective survival of a proportion of the developing sympathetic and sensory neurones as they innervate their particular target tissues. The underlying basis of this phenomenon is the synthesis of limited amounts of NGF in the target, its secretion around, and uptake by, the nerve terminal and its retrograde transport along axons to the neuronal cell bodies. The cascades of reactions which lead to neuronal survival and maintenance are initiated by signal transduction somewhere in this pathway. Retrograde transport and the initial signal transduction step begin when NGF binds to NGF receptors on the nerve terminal. Receptor-mediated internalization and the survival and maintenance function of NGF are mediated by the higher affinity receptors. These receptors have relative molecular masses of approx. 145,000 and are trypsin-resistant when occupied. In contrast, the larger population of lower affinity receptors have relative molecular masses of 85,000 and are rapidly degraded by trypsin. Clustering of the lower affinity receptors by a variety of agents gives them many of the characteristics of the higher affinity receptors, suggesting receptor interconversion may play a role in NGF actions. The structure of the lower affinity NGF receptor, determined by gene transfer and cloning, shows it to be a unique, heavily glycosylated protein. The extracellular domain is rich in cysteine-containing repeat units while the intracellular domain lacks the consensus sequence for an endogenous kinase activity. It is likely that the higher affinity receptor contains this protein as the NGF binding subunit together with a second protein which determines both the nature of the signal transduction mechanism and the process of internalization.