The Growth Cone Cytoskeleton in Axon Outgrowth and Guidance

Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. Over the past two decades, our knowledge of the many guidance cues, receptors, and downstream signaling cascades involved in neuronal outgrowth and guidance has increased dramatically. Less is known, however, about how those cascades of information converge and direct appropriate remodeling and interaction of cytoskeletal polymers, the ultimate effectors of movement and guidance. During development, much of the communication that occurs between environmental guidance cues and the cytoskeleton takes place at the growing tip of the axon, the neuronal growth cone. Several articles on this topic focus on the “input” to the growth cone, the myriad of receptor types, and their corresponding cognate ligands. Others investigate the signaling cascades initiated by receptors and propagated by second messenger pathways (i.e., kinases, phosphatases, GTPases). Ultimately, this plethora of information converges on proteins that associate directly with the actin and microtubule cytoskeletons. The role of these cytoskeletal-associated proteins, as well as the cytoskeleton itself in axon outgrowth and guidance, is the subject of this article.As evidenced by other articles on this topic, our understanding of the cues, receptors, and signaling events underlying axon outgrowth and guidance has grown dramatically in recent years. Here, we focus on recent research involving cytoskeletal dynamics downstream of guidance receptor signaling that has begun to unravel the mechanisms underlying guided growth cone movement during development. We begin by covering how growth cone morphology changes during outgrowth and guidance. Since cytoskeletal dynamics underlie changes in growth cone morphology, we discuss where different cytoskeletal polymers reside in the growth cone and what forms of dynamic reorganization they undergo. We then present a description of selected actin- and microtubule-associated proteins that have been identified in developing neurons and discuss how they may function in axon outgrowth and guidance. Finally, we present a working model of how growth cones integrate multiple signaling cascades to produce functionally useful output, and highlight some of the outstanding questions and challenges that face the field of growth cone cytoskeletal biology.