Extracellular Proteolysis in Axon Guidance and Synaptic Plasticity

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Proposal IBN 0091184PI: Keshishian, HaigAbstract:One of the ways a nervous system undergoes change is to modify the connections between nerve cells. This often requires the action of specialized secreted enzymes, which degrade or otherwise modify the local cellular environment, thus permitting modifications in the connections between neurons and their targets. An important class of these secreted enzymes is the "serine proteinases". These proteinases are widely conserved in evolution, and have been shown to be important in both the establishment and modification of neural connections during development, as well as in the later modifications associated with learning and memory. Serine proteinases are in turn regulated by a special class of proteins known as "serpins" (serine proteinase inhibitors). The serpins and serine proteinases, therefore, function as an interdependent system of secreted proteins of key importance in regulating nervous system change. In order to understand these proteins better Dr. Keshishian will examine their biological functions in a model genetic system, Drosophila. In Drosophila Dr. Keshishian has already identified the key "neuroserpin" of the nervous system, and has noted that it is expressed at connections between motoneurons and muscles. The major goal is to examine its functions at the developing neuromuscular connections, and to test the effects of both its loss and overexpression. The Drosophila neuroserpin is closely related to its mammalian counterpart, and insights gained in Drosophila about its function and regulation will be of value in understanding how the serpins influence nervous system development in general.