Regulation of the synthesis of nerve growth factor.

Through nearly 40 years of research nerve growth factor (NGF) has become a paradigm for neurotrophic factors. NGF is synthesized and released from innervated target tissues in limiting amounts, thereby regulating the cell number and the differentiated properties of responsive neurones. Three distinct cell types are responsive to NGF: peripheral sensory and sympathetic neurones and certain types of central cholinergic ones. The effects of NGF are mediated through interaction with a specific receptor which activates a transmembrane second-messenger system. NGF synthesis is regulated during development and in the adult animal. In the developing whisker pad, NGF synthesis commences with its sensory innervation, but sensory neurones lack NGF receptors at the stage when their fibres are growing to their target. These findings indicate that NGF does not attract sensory nerve fibres chemotactically to their target fields during development, but is involved in target-controlled neuronal cell death and in regulation of the density of innervation of target tissues. In non-neuronal cells of the sciatic nerve, NGF synthesis is up-regulated during development and after nerve lesion. Thus the changes in NGF levels after lesion in the adult animal are consistent with the hypothesis that the non-neuronal cells relapse into an earlier developmental stage. Regenerating fibres penetrating into the distal nerve stump restore the low adult levels of NGF. Recent evidence indicates that macrophages invading the nerve after transection produce signals which increase NGF synthesis.