An entirely different function of NGF came to light recently with the discovery that certain non-neuronal cells are able to respond to the protein. Lloyd A. Greene and Arthur S. Tischler of the Harvard Medical School demonstrated in 1977 that cells of the line designated PC12 (which are derived from a rat tumor) respond to NGF by acquiring properties characteristic of sympathetic neurons. The NGF-treated cells send out fibers, become electrically excitable and store and release neurotransmitters of the catecholamine type. When NGF is withdrawn from the culture medium, the cells retract their fibers, lose their other neuronal properties and resume the uncontrolled proliferation characteristic of neoplastic cells.
Shortly after this discovery K. Unsicker and his colleagues at Johns Hopkins University found that immature chromaffin cells obtained from the medulla (inner part) of the adrenal gland and cultured in the presence of NGF acquire the biochemical and morphological properties of sympathetic neurons. Subsequent experiments carried out at the Laboratory of Cell Biology in Rome by Luigi Aloe and one of us (Levi-Montalcini) demonstrated that this remarkable transformation can also take place in the intact animal: repeated injections of NGF into rat fetuses, continued for two to three weeks after birth, resulted in the differentiation of chromaffin cells into sympathetic neurons in the core of the adrenal gland! These findings indicate that NGF plays a much broader role in the living organism than had been supposed.
It should be obvious to the reader that the investigation of NGF, which began more than two decades ago, is far from over. Among the many unanswered questions is why NGF is manufactured and secreted by the venom gland of snakes and the salivary gland of rodents, even though neither of these glands is essential for the life of the organism and the sympathetic neurons that depend on NGF for their survival. The molecule is also manufactured and released in minute amounts by a wide range of normal and neoplastic cells.
The discovery of NGF has made it possible to experimentally manipulate sympathetic neurons with considerable ease, both in tissue culture and in the living animal. With the aid of purified NGF and NGF antibodies the neurobiologist is now able to increase the number of sympathetic neurons in an animal tenfold or to eliminate them altogether. Moreover, the catecholaminesecreting neurons in the brain are strikingly similar to the sympathetic neurons in the peripheral ganglia in both their morphological and biochemical properties. Already information gained from the study of sympathetic neurons has proved applicable to the treatment of disorders of the central catecholaminesecreting neurons, such as Parkinson's disease. A. Bjorklung, B. Bierre and U. Stenevi of the University of Lund recently obtained preliminary evidence that the catecholamine-secreting neurons in the brain respond to NGF with a profuse branching of their nerve fibers. If these findings are confirmed, a powerful tool will become available for modulating the function of such brain circuits, which play a crucial role in many kinds of behavior.