Molecular Navigation: How Axon Guidance Cues Shape Neural Circuits

Precise long-range axon guidance is essential for neural-circuit assembly, and its failure underlies disorders ranging from corpus-callosum agenesis to epilepsy and autism. Four ligand families, including netrins, slits, semaphorins and ephrins, provide combinatorial attract-repel signals that growth cones decode via receptor repertoires and cytoskeletal dynamics. Recent studies show how co-receptors, stoichiometry and second messengers pivot single cues between attraction and repulsion, yielding context-specific trajectories. Guidance programmes re-emerge in the adult brain during learning and after injury, supplying intrinsic blueprints for regeneration, yet their aberrant reactivation can drive maladaptive sprouting and network hyperexcitability. Therapeutic concepts now in pre-clinical testing include Eph inhibitors, exosome-delivered netrin-1 or Sonic Hedgehog, gene editing of guidance receptors and AI-assisted multi-cue scaffolds. This review integrates molecular and translational advances, linking defined wiring errors to clinical phenotypes and proposing how programmable guidance signals could achieve targeted and patient specific repair of damaged neural circuits, thereby laying a conceptual foundation for next generation regenerative neurology that unites developmental biology, biomaterials engineering, and data driven modelling.