Rho Family GTPases in Axon Guidance Inhibition

Spinal cord Injury (SCI) is a significant medical problem with few effective therapies and none that address the major problem: after SCI neurons do not regrow. This likely leads to the severe functional deficits that persist throughout the lives of persons with SCI. Some central nervous system cells (astrocytes and other non-neuronal cell types) become reactive and produce astroglial scars following SCI. These scars are associated with the production of substances that inhibit the regrowth of neurons, such as chondroitin sulfate proteoglycans (CSPGs). How these substances exert their inhibitory effects in unknown, but evidence indicates that they stop the backbone (cytoskeleton) of a neuronal cell ITom extending. A family of proteins (rho GTPases) is known to direct the remodeling of the neuronal cytoskeleton. Some family members (Racl and Cdc42) are associated with neuronal elongation, while other are associated with neuronal inhibition. The role of rho GTPases in SCI is unknown. We hypothesize that rho family GTPases are differentially regulated to direct inhibition of neuronal cytoskeletal extension by CSPG. We will address this concern by determining I) where rho GTPases are located, and if they are active, in the cell in normal and injured spinal cords and neurons in cell culture; 2) the effect of altering the activation of rho GTPases in neurons on their behavior upon contact with CSPG; and 3) the effects of rho GTPases on the cytoskeleton. Results from these experiments will define the role of these proteins in the inhibition of neuronal regrowth caused by inhibitors associated with astroglial scarring, and may lead to new therapies to improve neuronal regrowth and functioning after SCI.