The Role of Serine Protease Inhibitors in Nervous System Development

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Nerve cells communicate with each other at specialized structures known as synapses. At the synapse cells are anchored to each other by specialized proteins that function like glues. During development it is necessary to unstick or modify these adhesive proteins, so that nerve branches can grow and new connections can be made. Similar changes occur at some synapses in the brain when new memories are formed.The adhesive proteins are broken down by enzymes known as proteases. The proteases are made by nerve cells and are released at the synapse. The released proteases do not degrade synaptic proteins in an uncontrolled fashion. Instead, they encounter other proteins known as "serpins", which inhibit the proteases. Thus, in areas where serpin levels are high, the protease activity is reduced. Serpins are made by many kinds of nerve cell, both in mammals and in invertebrates. For example, the most common serpin of the human brain (Neuroserpin) is closely related to the serpin found in the brain of the fruit fly Drosophila, known as Spn4. In this proposal the PI will examine the synapses made between nerve cells and muscles in Drosophila. Spn4 is found at these synapses, where we hypothesize that it inhibits one or more proteases involved in the normal development of the synapse.The role that the Spn4 plays in both the development and function of nerve-muscle synapses will be examined in situations where the amount of the protein is either increased or reduced during development. This project will examine how nervous system activity influences the amount or function of Spn4 using various genetic mutations. Finally, the PI will identify the proteases that are inhibited by Spn4. Broader Impacts of Proposed Activity: Education and outreach. The investigator has extensive experience training undergraduates, graduate students, and postdoctoral fellows, including members from underrepresented minority groups (including one graduate student in this proposal). He encourages undergraduate research, including publication of papers supported by the previous NSF funding (1 undergraduate first author, 1 coauthor). The project will support the continued training of students in the areas of cellular neurobiology, neural development, and genetics, preparing them for advanced scientific careers. Research community: Many of the reagents and transgenic lines developed in the lab are of widespread utility, and are freely available to researchers, furthering scientific inquiry. Finally, fundamental knowledge about the molecular and cellular mechanisms governing of synaptic development and plasticity provides a firm foundation for developing future neurobiological applications of general benefit to society.