Gorla Madhavi, Guleria Digvijay Singh
National Institute of Animal Biotechnology, Hyderabad, India.
J Cell Physiol. 2025 Jan;240(1):e70005. doi: 10.1002/jcp.70005.
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.
轴突导向是一个高度动态的过程，由细胞表面导向受体与细胞外环境中存在的导向线索之间的相互作用所调控。在发育过程中，精确的轴突导向对于功能性神经回路的形成至关重要。轴突导向受体的时空表达有助于导航轴突在包含吸引性和排斥性导向线索的复杂环境中做出正确决策。轴突导向受体启动不同的信号级联反应，最终影响轴突生长末端（称为生长锥）的细胞骨架。肌动蛋白细胞骨架是这些导向信号的主要靶点，在生长锥的运动、探索和行为中起关键作用。在众多响应不同导向信号调节肌动蛋白细胞骨架的调节分子中，Rho GTP酶发挥着核心作用。Rho GTP酶是分子开关；它们的开启（结合GTP）和关闭（结合GDP）开关由它们与调节GDP与GTP交换的蛋白质或促进GTP水解的蛋白质的相互作用控制。各种上游信号，包括轴突导向信号，调节这些Rho GTP酶开关调节因子的活性。作为循环分子开关，Rho GTP酶与下游效应器相互作用并控制其活性，下游效应器以依赖于上下文的方式直接影响肌动蛋白重组。对Rho GTP酶信号传导的时空动态及其参与调节生长锥肌动蛋白细胞骨架的分子基础进行更深入的探索，可以为与Rho GTP酶信号失调相关的神经发育障碍解锁有前景的治疗策略。本综述不仅全面概述了该领域，还突出了最近的发现，这些发现极大地推进了我们对Rho GTP酶在轴突导向过程中调节生长锥肌动蛋白细胞骨架排列的复杂调节作用的理解。
