Rho GTPase Signaling: A Molecular Switchboard for Regulating the Actin Cytoskeleton in Axon Guidance

Axon pathfinding is a highly dynamic process regulated by the interactions between cell-surface guidance receptors and guidance cues present in the extracellular environment. During development, precise axon pathfinding is crucial for the formation of functional neural circuits. The spatiotemporal expression of axon guidance receptors helps the navigating axon make correct decisions in a complex environment comprising both attractive and repulsive guidance cues. Axon guidance receptors initiate distinct signaling cascades that eventually influence the cytoskeleton at the growing tip of an axon, called the growth cone. The actin cytoskeleton is the primary target of these guidance signals and plays a key role in growth cone motility, exploration, and behavior. Of the many regulatory molecules that modulate the actin cytoskeleton in response to distinct guidance signals, Rho GTPases play central roles. Rho GTPases are molecular switchboards; their ON (GTP-bound) and OFF (GDP-bound) switches are controlled by their interactions with proteins that regulate the exchange of GDP for GTP or with the proteins that promote GTP hydrolysis. Various upstream signals, including axon guidance signals, regulate the activity of these Rho GTPase switch regulators. As cycling molecular switches, Rho GTPases interact with and control the activities of downstream effectors, which directly influence actin reorganization in a context-dependent manner. A deeper exploration of the spatiotemporal dynamics of Rho GTPase signaling and the molecular basis of their involvement in regulating growth cone actin cytoskeleton can unlock promising therapeutic strategies for neurodevelopmental disorders linked to dysregulated Rho GTPase signaling. This review not only provides a comprehensive overview of the field but also highlights recent discoveries that have considerably advanced our understanding of the complex regulatory roles of Rho GTPases in modulating actin cytoskeleton arrangement at the growth cone during axon guidance.