Li Jiyuan, Gao Hanqi, Liu Fang
Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
Medical Experimental Teaching Center, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
Cells. 2025 May 25;14(11):777. doi: 10.3390/cells14110777.
Axon guidance, a fundamental process in neural circuit formation, is intricately regulated by Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) through dynamic cytoskeletal remodeling. FGF signaling, mediated by heparan sulfate proteoglycans or Klotho co-factors, activates key downstream pathways: PI3K-Akt, JAK-STAT, PLCγ, and RAS-MAPK. These pathways orchestrate actin filament dynamics, microtubule stability, and the organization of intermediate filaments. These pathways converge on Rho GTPases, cofilin, profilin, and tau to balance the cytoskeletal assembly-disassembly cycles, enabling growth cone navigation. Unresolved questions, such as the mechanisms underlying FGF-mediated growth cone steering, highlight critical future research directions. This review integrates structural, molecular, and functional insights into how FGF-FGFR interactions regulate axon pathfinding, emphasizing the crosstalk between signaling cascades and cytoskeletal plasticity. Elucidating these mechanisms not only advances our understanding of neural development but also opens therapeutic avenues for neuro-developmental disorders, nerve injury, and neurodegenerative diseases by targeting FGF-driven cytoskeletal dynamics.
轴突导向是神经回路形成中的一个基本过程，成纤维细胞生长因子（FGFs）及其受体（FGFRs）通过动态细胞骨架重塑对其进行复杂的调控。由硫酸乙酰肝素蛋白聚糖或α-klotho辅助因子介导的FGF信号传导激活关键的下游通路：PI3K-Akt、JAK-STAT、PLCγ和RAS-MAPK。这些通路协调肌动蛋白丝动力学、微管稳定性以及中间丝的组织。这些通路汇聚于Rho GTP酶、丝切蛋白、前纤维蛋白和微管相关蛋白tau，以平衡细胞骨架的组装-拆卸循环，从而实现生长锥导航。诸如FGF介导的生长锥转向的潜在机制等未解决的问题，突出了未来关键的研究方向。本综述整合了结构、分子和功能方面的见解，阐述了FGF-FGFR相互作用如何调节轴突寻路，强调了信号级联与细胞骨架可塑性之间的相互作用。阐明这些机制不仅能增进我们对神经发育的理解，还能通过靶向FGF驱动的细胞骨架动力学，为神经发育障碍、神经损伤和神经退行性疾病开辟治疗途径。
