Regulation of Growth Cone Actin Filaments by Guidance Cues Gianluca Gallo, 1 Paul C. Letourneau 2 1 Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129 2 Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street, Minneapolis, Minnesota 55455 Received 7 April 2003; accepted 8 April 2003 ABSTRACT: The motile behaviors of growth cones at the ends of elongating axons determine pathways of axonal connections in developing nervous systems. Growth cones express receptors for molecular guidance cues in the local environment, and receptor-guidance cue binding initiates cytoplasmic signaling that regulates the cytoskeleton to control growth cone advance, turn- ing, and branching behaviors. The dynamic actin fila- ments of growth cones are frequently targets of this regulatory signaling. Rho GTPases are key mediators of signaling by guidance cues, although much remains to be learned about how growth cone responses are orches- trated by Rho GTPase signaling to change the dynamics of polymerization, transport, and disassembly of actin filaments. Binding of neurotrophins to Trk and p75 receptors on growth cones triggers changes in actin filament dynamics to regulate several aspects of growth cone behaviors. Activation of Trk receptors mediates local accumulation of actin filaments, while neurotro- phin binding to p75 triggers local decrease in RhoA signaling that promotes lengthening of filopodia. Sema- phorin IIIA and ephrin-A2 are guidance cues that trig- ger avoidance or repulsion of certain growth cones, and in vitro responses to these proteins include growth cone collapse. Dynamic changes in the activities of Rho GTPases appear to mediate responses to these cues, although it remains unclear what the changes are in actin filament distribution and dynamic reorganization that result in growth cone collapse. Growth cones in vivo simultaneously encounter positive and negative guid- ance cues, and thus, growth cone behaviors during ax- onal pathfinding reflect the complex integration of mul- tiple signaling activities. © 2003 Wiley Periodicals, Inc. J Neurobiol 58: 92–102, 2004 Keywords: growth cone; actin filaments; Rho GTPases; pathfinding; cytoskeleton INTRODUCTION Growth cones are specialized motile structures at the ends of developing axons. The activity of growth cones is the main determinant of axon guidance and elongation. As an axon extends through the complex extracellular environment in vivo, its growth cone samples the local environment and responds to a variety of molecular guidance cues. Growth cones sample their environment by extending slender fin- gerlike projections called filopodia and veil-like struc- tures termed lamellipodia. Both lamellipodia and filopodia are strictly dependent on the polymerization and organization of actin filaments (F-actin; Fig. 1). Evidence indicates that F-actin is a major intracellular target for the effects of extracellular guidance cues that alter growth cone behavior. Correspondence to: P. C. Letourneau (letour@lenti.med.umn. edu). Contract grant sponsor: NIH (G.G. and P.C.L.). Contract grant sponsor: NSF (P.C.L.). Contract grant sponsor: Minnesota Medical Foundation (P.C.L.). Contract grant sponsor: Spinal Cord Research Foundation (G.G.). © 2003 Wiley Periodicals, Inc. DOI 10.1002/neu.10282 92