ROLE OF RHO FAMILY GTPASES DURING NEURONAL DEVELOPMENT

Complex neuronal networks form during development, to establish a functional nervous system. Each neuron participates by sending neurites towards specific targets, where synapses will form. The growth cone is the exploratory organ of the developing neurite. It responds rapidly to extracellular cues, and modifies the migratory behaviour by modulating the cytoskeleton. While a large amount of information is available on the extracellular mechanisms driving the elongation of the neurites, large gaps exist in the comprehension of the underlying intracellular events. Neuritogenesis requires the concerted progression of a number of cellular events including the organization of the cytoskeleton, adhesion to the surrounding environment, and membrane traffic. GTPases of the Rho family have been implicated in the regulation of the cytoskeleton and adhesion during the maturation of neurons. The perturbation of the activity of these proteins in neurons affects the development of neurites and synapses. Our laboratory is focusing on the function of these GTPases during neuronal differentiation. We have identified one of these GTPases, Rac1B, which is specifically expressed in the nervous system, and is important for the formation of neurites. The first goal of this project is the analysis of the function of Rac1B function in vivo, using mice with a mutant Rac1B gene, that we are producing in the lab. The second goal is the characterization of the molecular mechanisms coordinating adhesion, cytoskeleton, and membrane traffic for the formation of a functional neurite. In this direction, we have identified a protein complex interacting with Rac GTPases, and necessary for Rac1B-mediated neurite extension. These studies will increase the knowledge of the mechanisms that regulate neuronal function, and are fundamental to the understanding of the degenerative processes associated to diseases of the nervous system.