The questions addressed in this proposal is a fundamental one in the field of neurobiology, namely how complex neural circuits are assembled during development. Developing neurons of both vertebrates and invertebrats possess the ability to recognize and follow specific pathways, often over long distances, which lead them to their appropriate synaptic targets. While the cell surface guidance molecules involved in these pathway selection events are largely unknown, a combinatorial code of LIM-homodomains (LIM-HD) proteins has been shown to control the axon pathway selection of neurons, likely by regulating the expression of specific guidance receptors. The goal of this project is to identify the guidance molecules regulated by Apterous (Ap), a Drosophila member of the LIM-HD family, as well as to characterize a set of putative axon guidance molecules isolated in a screen for genes that switch the pathway selection of the Ap neurons. Using Drosophila genome arrays, the differences in gene expression between FACS-sorted Ap neurons from wild-type and from ap mutants will be determined at the level of the entire genome. A parallel genetic screen will also be carried out. Misexpression of Ap in a subset of neurons that do not normally express it switches their axon projections to the pathway normally taken by the Ap neurons, supporting the hypothesis that Ap is ectopically regulating genes encoding guidance molecules normally expressed by the Ap neurons. To test this and to identify the genes regulated by Ap, EMS-induced mutations that dominantly suppress the gain-of-function axon-switching phenotype will be isolated and analyzed. From a screen for genes causing pathway switching of the AP neurons, several known and putative axon guidance molecules have been isolated, including the Drosophila ortholog of the Unc5 receptor for the Netrins. These molecules will be tested for their roles in axon guidance by generating mutations in their genes. Given the functional conservation throughout the animal kingdom of many protein families, including the ILM-HD family, these studies will provide us with a better understanding of axon guidance mechanisms not only in Drosophila, but in higher vertebrates as well.
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