Regulation of Rho by p190 RhoGAPs and the Smurf1 ubiquitin ligase in neurons

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During the differentiation of neurons, Rho GTPases play an essential role in the remodelling of the actin cytoskeleton in response to intrinsic and extrinsic signals. The most dramatic morphological change in the development of mature neurons is the formation of axons and dendrites. In cultures of dissociated hippocampal neurons, initially several neurites of similar length are formed that are equivalent until one of them becomes the axon at 2 DIV and extends rapidly. One day later, the remaining neurites begin to grow as they differentiate into dendrites. The extension of dendrites can be stimulated further by extrinsic factors such as the axon guidance molecule Semaphorin 3A. The importance of Rho GTPases for neuronal differentiation has been documented extensively. However, the signalling pathways that mediate the regulation of Rho to allow the extension of neurites during differentiation and in response to extracellular signals are only partially understood. The proposed project intends to elucidate how the RhoGAPs p190 and p190-B together with the ubiquitination of Rho by Smurf1 determine the level of active Rho during the extension of neurites. In addition, we want to understand how these pathways are regulated by extracellular factors like Semaphorin 3A.