Grant: Operating Grant

Directed cell motility is an essential biological function for a variety of cells and tissues. This is particularly important in the development of the nervous system and the formation of neural circuits. During development neurons must extend long cellular processes and establish precise connections with other neurons in order to wire up the brain correctly. This process relies on the precise distribution of guidance cues to direct neuronal growth to the appropriate target followed by the establishment of the appropriate synapses. From this stage on throughout the life of the organism the axon must maintain its morphology so that persistent communication can occur between groups of neurons. How this morphology is maintained in the mature nervous system and how it may be regenerated or modified after traumatic injury or disease related degeneration is not understood. The aim of this research proposal is to identify the intracellular signalling mechanisms that are important for regulating neuronal morphology in the mature nervous system. We have previously shown that a specific protein called calpain negatively regulates neuronal growth in developing neurons. That is, the activity of this protein prevents the formation of neuronal branches and additional axons as neurons grow. We will extend these observations by examining whether calpain inhibits neuronal branching and growth in an intact developing nervous system. In addition, we will test the novel hypothesis that this protein activity is also necessary to prevent branch formation and growth in the mature nervous system. This would be the first series of experiments that would directly test whether active signaling is necessary to maintain the normal morphology of the mature nervous system.