The neurotrophic hypothesis: Where does it stand?

In the developing peripheral nervous system many neurons die shortly after their axons reach their target fields. This loss is thought to match the number of neurons to the size and requirements of their target fields because altering target field size before innervation affects the number of neurons that survive. The neurotrophic hypothesis provides an explanation for how target fields influence the size of the neuronal populations that innervate them. This hypothesis arose from work on nerve growth factor (NGF), the founder member of the neurotrophin family of secreted proteins. Its principal tenet is that the survival of developing neurons depends on the supply of a neurotrophic factor that is synthesized in limiting amounts in their target fields. The neurotrophic hypothesis has, however, been broadened by the demonstration that multiple neurotrophic factors regulate the survival of certain populations of neurons. For example, some neurons depend on several different neurotrophic factors which may act concurrently or sequentially during target field innervation. In addition, there are aspects of neurotrophin action that do not conform with the classic neurotrophic hypothesis. For example, the dependence of some populations of sensory neurons on particular neurotrophins before significant neuronal death takes place raises the possibility that the supply of these neurotrophins is not limiting for survival at this stage of development. There is also evidence that at stages before and after sensory neurons depend on target-derived neurotrophins for survival, neurotrophins act on at least some sensory neurons by an autocrine route. Yet despite the growing wealth of information on the multiple roles and modes of action of neurotrophic factors, the neurotrophic hypothesis has remained the best explanation for how neuronal target fields in the developing peripheral nervous system regulate their innervation density.