The Nerve-Growth Factor: A New Tool for Manipulating Neurons

This protein plays a key role in the formation of the nervous system. It has also been employed as an "Ariadne's thread" to explore mechanisms of nerve-cell growth and differentiation

By Rita Levi-Montalcini and Pietro Calissano

HALO OF NERVE FIBERS radiates from a sympathetic-nerve ganglion that was removed from a chick embryo and then incubated for 12 hours in a semisolid medium containing the nerve-growth factor (NGF). The factor was originally isolated from a mouse tumor designated sarcoma 180 but has subsequently been found to be secreted in trace amounts by a variety of normal and neoplastic (cancer) cells. In 1953 one of the authors (Levi-Montalcini) and Hertha Meyer found that NGF could induce the outgrowth of nerve fibers from an isolated sympathetic ganglion in tissue culture. This discovery led ultimately to the isolation of NGF and determination of its chemical structure. Micrograph, which magnifies ganglion 135 diameters, was made by J. S. Chen at Laboratory of Cell Biology in Rome. Image: Scientific American, June 1979

Editor's Note: Neurobiologist Rita Levi-Montalcini, a Nobel laureate in physiology or medicine in 1986, died December 30 at the age of 103. We are making this article co-authored by her free online for the next 30 days. This story was originally published in June 1979 issue of?Scientific American.

The human nervous system is a vast network of several billion neurons, or nerve cells, endowed with the remarkable ability to receive, store and transmit information. In order to communicate with one another and with non-neuronal cells the neurons rely on the long extensions called axons, which are somewhat analogous to electrically conducting wires. Unlike wires, however, the axons are fluid-filled cylindrical structures that not only transmit electrical signals but also ferry nutrients and other essential substances to and from the cell body. Many basic questions remain to be answered about the mechanisms governing the formation of this intricate cellular network. How do the nerve cells differentiate into thousands of different types? How do their axons establish specific connections (synapses) with other neurons and non-neuronal cells? And what is the nature of the chemical messages neurons send and receive once the synaptic connections are made?

This article will describe some major characteristics and effects of a protein called the nerve-growth factor (NGF), which has made it possible to induce and analyze under highly favorable conditions some crucial steps in the differentiation of neurons, such as the growth and maturation of axons and the synthesis and release of neurotransmitters: the bearers of the chemical messages. The discovery of NGF has also promoted an intensive search for other specific growth factors, leading to the isolation and characterization of a number of proteins with the ability to enhance the growth of different cell lines.

The peripheral nervous system of vertebrate animals includes three kinds of nerve cells: sensory neurons, which transmit impulses from sensory receptor structures to the brain; motor neurons, which innervate the striated, or skeletal, muscles, and autonomic neurons, which regulate the functional activity of the circulatory system, the organs, the glands and the smooth muscles (such as those of the intestine). Autonomic neurons are of two kinds: sympathetic and parasympathetic. The sensory neurons and some of the sympathetic neurons are situated in chains of ganglia flanking the length of the spinal cord. Because these neurons are uniquely accessible to experimental manipulation much of the research on the development of the nervous system at the cellular level has focused on how the nerve fibers projecting from the sensory and sympathetic ganglia make connections with their corresponding target organs.

In the first half of this century the new science of experimental embryology seemed to offer the best way to study the intimate bond that interlocks the growth of the peripheral neurons and their target organs. Ross G. Harrison of Yale University challenged the nervous system of the larva of amphibians to solve problems it would ordinarily never confront, such as providing nerves for limbs and organs grafted from other species. He wanted to see how sensory and sympathetic ganglia, sending out their nerve fibers to these peripheral "fields of innervation," would adjust to the different dimensions and configurations of the foreign organs.

Harrison's results demonstrated that the developing amphibian nervous system is remarkably flexible in adapting to such novel situations, even to the point of accelerating the growth of nerve fibers in a host species to keep pace with the faster-growing limb of a smaller donor species. He concluded that the embryonic nervous system is highly receptive to influences exerted by the peripheral field. Such influences are not species-specific, however, since they can be evoked by organs or rudimentary limbs that have been transplanted from one species to another.

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