Axonal Regeneration, Growth Cone, and the FIGN Gene Family: A Comprehensive Review

Mature mammalian central nervous system (CNS) neurons exhibit limited regenerative capacity, resulting in severe and often irreversible functional deficits following injuries such as spinal cord injury or stroke. Both inhibitory extrinsic environments and intrinsic neuronal constraints govern this regenerative failure. Growth cones-cytoskeleton-rich structures at axonal tips-are critical for axon extension and pathfinding during neural repair, with their structural integrity and motility heavily dependent on microtubule (MT) stability and dynamics. Pharmacological stabilization of MTs has been shown to prevent growth cone collapse and support regeneration, highlighting MTs as a promising therapeutic target. The FIGN gene family-FIGN, FIGNL1, and FIGNL2-encodes microtubule-severing enzymes (MSEs) that regulate MT remodeling, thereby directing axonal growth and regeneration. FIGN and FIGNL2 act as key negative regulators: FIGN destabilizes dynamic tyrosinated MTs, whereas FIGNL2 selectively severs stable acetylated MTs, both leading to excessive microtubule fragmentation, growth cone collapse, and impaired regeneration. Inhibition of FIGN or FIGNL2, particularly via siRNA-mediated knockdown, enhances MT integrity, promotes robust axonal regrowth, and improves functional recovery in preclinical models. In contrast, FIGNL1 modulates MT dynamics in a context-dependent manner, primarily contributing to developmental neurite outgrowth. These proteins intersect with critical signaling pathways, including RhoA/ROCK and PI3K/Akt, linking cytoskeletal regulation to regenerative signaling. Targeting FIGN or FIGNL2 represents a promising neuropharmacological strategy to overcome intrinsic barriers to CNS repair. This review elucidates the regulatory mechanisms and functional roles of the FIGN gene family in neural regeneration and proposes novel therapeutic approaches for CNS injury and neurodegenerative diseases.