7.4 Elixirs of the nervous system: neurotrophins

According to Section 7.2 axons obtain an elixir from targets at their synapses.

Confirmation that there is indeed an elixir came from a series of events that reveals how much of science really works. Elmer Bucker, working with Hamburger in the mid-1940s, had removed a limb bud from a chick and replaced it with a tumour from the muscle of a mouse – just to see what happened. What happened was that the tumour caused an enlargement of both the sympathetic and sensory ganglia (neuron pools) that normally innervate the limb. Another investigator, Rita Levi-Montalcini picked up on this result and used an extract from the tumour in later experiments on dorsal root ganglia in tissue culture (Levi-Montalcini, 1975). The extract caused a massive increase in the growth of neurites. This led to the extract, or more specifically some component of the extract, being called nerve growth factor. The tumour was treated with various enzymes to find out if different components of the extract were more potent than others. Snake venom was used as a source of some of these enzymes. To everyone's surprise the snake venom itself proved to be a more potent growth-stimulating factor than extracts from the tumour cells. As snake venom is synthesised in the salivary glands, Levi-Montalcini tried an extract from mouse salivary glands. The mouse salivary glands did indeed prove to be a plentiful source of nerve growth factor and a suitable source to use for the difficult process of purification. (Quite why the salivary glands contain nerve growth factor remains an unanswered question.) Rita Levi-Montalcini shared the Nobel prize for Physiology or Medicine for the discovery of nerve growth factor in 1986.

Is nerve growth factor (NGF) the elusive elixir? Three kinds of studies – deprivation studies, enhancement studies, as well as knockout mice studies – proved that it was, for neurons of the sympathetic nervous system at least. Depriving mice of NGF by injecting anti-NGF antibodies (i.e. antibodies that react with NGF) resulted in adult mice almost lacking in sympathetic neurons. Conversely, increasing the amount of NGF in the embryo caused enlargement of sympathetic ganglia. Neurons in these enlarged ganglia were both more numerous and larger. Knockout mice in which the gene encoding NGF has been deleted are lacking in the majority of sympathetic neurons. NGF is indeed the elixir and in time-honoured fashion is called something else, a trophic factor. (Also sometimes called a chemotrophic factor, a neurotrophic factor and a neurotrophin.) We will mostly use neurotrophin for the rest of this section.

The neurotrophin hypothesis was necessary to explain the results of experiments on the limb bud and its innervating motor and sensory neurons. (See Section 7.2, where it was first mentioned as a quaint hypothesis.) Nerve growth factor has been shown to affect only the growth and survival of sympathetic neurons, not motor or sensory neurons.

Think about what this last sentence implies.

To explain the limb bud transplantation experiments, the neurotrophin (elixir) hypothesis was constructed. The NGF story proves that such elixirs, such neurotrophins, exist. The NGF story also proves that NGF is not the neurotrophin for motor or sensory neurons. There must be other neurotrophins.

The hunt for neurotrophins is intense, but it took ten years for the second (brain-derived neurotrophic factor, BDNF) to be discovered. More recent additions are neurotrophin-3, neurotrophin-4, neurotrophin-6 and neurotrophin-7.