| Summary: | The nervous system of an organism is exceedingly complex and yet highly specific in the connections that it makes. The mechanisms by which a functional nervous system is developed are therefore of great importance and interest. Neurons extend processes over long distances and through various environments in order to form connections with their appropriate targets. The neurites must sense their environment and make decisions based on guidance cues as to which direction to grow. The growth cone of the developing neurite is a dynamic, actin-rich domain at the leading edge and is the site for integration of various guidance cues and, therefore, of this decision making. The molecular mechanisms underlying outgrowth, in particular consolidation of developing axons – the process in which the actin network of the proximal region of the growth cone collapses creating a new segment of axon, remain unclear. Our lab previously uncovered a role for the actin-associated protein cortactin as an enhancer of membrane protrusions in cultured neurons and for calpain as an inhibitor of this process in consolidated regions. However, the physiological roles for cortactin and calpain in axon outgrowth and cell migration have remained elusive as others have observed both similar and opposite effects of these proteins. These discrepancies are likely due to the variability associated with in vitro studies. Therefore, I set out to elucidate the function of these molecules in developing axons in vivo within the model organism Drosophila melanogaster. Using two subsets of neurons within the central nervous system, I observed that the overexpression of cortactin combined with the inhibition of calpain increased the elongation of axons as well as the incidence of misguidance. Therefore, it appears that in vivo, cortactin acts as an enhancer of membrane protrusions and elongation and is actively inhibited by calpain. In addition, these two proteins appear to influence guidance, though through what mechanism remains to be investigated. Knowledge of the molecular pathways involved in axon outgrowth and guidance is key to the understanding of not only development, but also plasticity and repair within the nervous system. === Medicine, Faculty of === Graduate
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