The Genetic Specification of Neuron-target Interactions: The Role of LOLA

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ABSTRACT IBN-9723376 GINIGER During the development of the brain and nervous system, a nerve cell often must extend its axon over a long distance to find a particular target. In the development of a limb, for example, each muscle must become innervated by a specific set of motor neuron for the limb to function properly. During the course of its growth, the tip of a neuron's axon makes a whole series of decisions about where and which way to turn, and about when to stop and form a synaptic connection. We know that the neuron responds to a complex constellation of external signals at each of these decision points. We do not understand, however, what mechanism coordinates the expression of all of these signals, and what ensures that the nerve cell has the proper machinery to recognize the appropriate set of signals at a particular time. Previous work has identified a single gene in the fruitfly Drosophila that seems to coordinate particular neuron guidance decisions. In the absence of this gene (called lola), specific nerves fail to recognize their targets, whereas in animals that make too much lola, these same nerves seem to interact too strongly with their targets. The structure of the LOLA protein suggests that it works by turning on and off the expression of other genes, perhaps the genes whose products are directly responsible for neuron-target recognition. The goal of Dr. Giniger's experiments is to understand what properties of lola provide specificity to nerve-target interactions. In particular, these experiments will test the idea that the matching of nerve to target occurs because one form of lola is made in target cells and causes them to produce signal molecules, while a second form of lola is made in nerve cells that causes them to produce signal-receivers. These experiments will also test the idea that lola can coordinate several different growth decisions because, in each case, it works together with a different partner protein. The brain is the most complex stru cture in biology, and we understand little about how its organization is established. These experiments will test a simple model for the mechanism by which genes determine brain structure. It is likely that the principles tested here in the fly will be equally applicable to the development of the brain in all animals.