Signal Transduction Pathways: From Receptor to the Actin Cytoskeleton

Abstract

In order to make functional connections in the developing nervous system, neurons must be actively guided through the extracellular environment to reach their appropriate targets. The growth cone, amotile structure located at the tip of axons, responds to extracellular guidance cues that can act as either attractants or repellents thereby steering the axon. As in motile non-neuronal cells, motility is achieved through actin and microtubule cytoskeletal rearrangements. The driving forces in growth cone advance, turning, and retraction all require changes in actin dynamics (Tessier-Lavigne and Goodman 1996, Dent and Gertler 2003, Dontchev and Letourneau 2003, Huber et al. 2003). Rho GTPases are proteins that have been shown to be principal actin regulators in both neuronal and non-neuronal cells (Mackay and Hall 1998, Burridge and Wennerberg 2004,Goveketal. 2005,Hall 2005, Jaffe and Hall 2005). These GTPases can regulate actin through effectors that can directly bind to or activate more downstream actin-binding proteins (Van Aelst and D’Souza-Schorey 1997, Takai et al. 2001). Activation of Rho GTPases can thereby coordinate actin dynamics by enhancing polymerization or by inhibit- ing monomer binding to filaments as well as by regulating actin disassembly and acto-myosin contractility. These GTPases have been shown to be essential in guid- ance decisions and, through their effects on actin and microtubules, orchestrate directional motility in growth cones.