The trip of the tip: understanding the growth cone machinery

Key Points During axon guidance, the growth cone, which comprises both the 'vehicle' and the 'navigator', progresses through stages of protrusion, engorgement and consolidation to move forward in a spatially directed manner. Growth cone guidance is an integrated process that requires both substrate-bound cues (such as cell adhesion molecules (CAMs), laminin and fibronectin) to provide the 'road' for traction, and chemotropic cues (such as netrins and semaphorins) that present 'road signs' for steering directions. Filamentous (F)-actin retrograde flow, which is driven by myosin II contractility in the transition (T) zone, and F-actin bundle treadmilling keep the growth cone engine idling and thus responsive to directional cues. Growth cone receptor binding to an adhesive substrate leads to the formation of a complex that acts like a molecular 'clutch', which mechanically couples receptors and F-actin to stop retrograde flow and drives actin-based forward growth cone protrusion. Microtubules (MTs) have a role in steering the growth cone vehicle; individual peripheral (P) domain MTs might act as guidance sensors and carry signals to and from receptor binding sites, and bulk central (C) domain MTs steer growth cone advance. Live imaging studies suggest that the function of actin dynamics is to guide and control MTs to steer the growth cone in the right direction, and interactions between actin and MTs are tightly regulated. F-actin bundles regulate the activities of exploratory MTs, whereas F-actin arcs constrain C domain MTs. For spatial discontinuities in the environment to drive growth cone steering and, in particular, to accurately interpret numerous cues simultaneously, the growth cone navigation system integrates and translates the multiple environmental directions to locally modulate the dynamics of the cytoskeletal machinery. The Rho family of GTPases control cytoskeletal dynamics downstream of nearly all guidance signalling pathways, and they are spatially regulated by guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs). Localized control of actin dynamics at the leading edge through actin-binding proteins, and coordination of MT–actin crosslinking, are two key outputs of the navigation system that are required for growth cone steering. The journey of the growth cone is similar to a vehicle on a road. Cytoskeletal elements form the 'motor' to move forward and provide traction on the road, whereas a 'navigator' system guide