In both vertebrates and invertebrates, projections from retinal neurons are arranged in the brain in the form of maps: neighbor relationships in the eye are preserved in the relationships of the terminal projections, and hence such maps are called retinotopic. Animals which fail to form such maps properly are blind. Despite the structural differences between vertebrate and insect eyes, we have shown that the strategies used to establish these maps show striking similarities. In both, retinal axons use some form of active recognition to reach their targets, and the maps formed are initially diffuse but are later refined by competition. While these basic principles have become clearer, we still understand very little about the molecular details of these processes, despite intensive study over many decades. it is the long term goal of this laboratory to establish a genetic model for retinotopic map development, using the elegant visual system of the fruit fly, Drosophila melanogaster. Using such a model system, the importance of particular gene products can be directly tested by their elimination in vivo, and new unsuspected molecules can be identified by screening without preconception for mutants that form abnormal maps. Such screens are likely to detect not only molecules involved in the development of such maps, but also moleculs that play more general roles in the trophic interactions involved in synapse stabilization and maintenance. These neural growth factors are likely to be of enormous importance in the understanding and treatment of visual dysfunction, as well as of neural disease and injury in general. The present proposal addresses the mechanisms of Drosophila R7/R8 map regulation. In conditions in which there is hyperinnervation of the insect map, terminals will send out collaterals into neighboring termination sites, but only if such sites are vacant, suggesting that neighboring sites interact to regulate the ability to stabilize collaterals during map development. We will first analyze the role of synaptic load and intrasite competition in the behavior of the axon terminals, using mosaic analysis of mutations that overload the terminal sites. In analogy with what is known in vertebrates, the role of both visually-evoked and developmental activity in these processes will be analyzed using dark-rearing, phototransduction mutations, mutations that alter the activity of ion channels known to be present in the photoreceptor neurons during development, and mutations that eliminate the major neurotransmitter of the photoreceptor neurons. To further define the competitive process, the time of synapse formation of R7 and R8 axons will be determined, and the ability of mutant terminals, and of collaterals from the hyperinnervated map, to form synapses will also be assessed. The relationship of collateral sprouting to the process of terminal refinement twill also be examined. Finally, as a first step toward identifying unknown genes involved in these processes, a genetic screen for mutants that alter axon targeting, the regulation of terminal sprouting, or synapse maintenance will be carried out.
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