Abstract: Spinal cord injury is a severe neurological condition with limited neuronal regeneration and functional recovery. Currently, no effective treatments exist to improve spinal cord injury prognosis. Neuronal guidance proteins are a diverse group of molecules that play crucial roles in axon and dendrite growth during nervous system development. Increasing evidence highlights their regulatory functions in spinal cord injury. This review provides a brief overview of the modulation patterns of key neuronal guidance proteins in neuronal axon growth during nervous system formation and subsequently focuses on their roles in neuronal regeneration and functional recovery following spinal cord injury. Neuronal guidance proteins include, but are not limited to, semaphorins and their receptors, plexins; netrins and their receptors, deleted in colorectal cancer and UNC5; Eph receptors and their ligands, ephrins; Slit and its receptor, Robo; repulsive guidance molecules and their receptor, neogenin; Wnt proteins and their receptor, Frizzled; and protocadherins. Localized Netrin-1 at the injury site inhibits motor axon regeneration after adult spinal cord injury while promoting oligodendrocyte growth. Slit2 enhances synapse formation in the injured spinal cord of rats. EphA7 regulates acute apoptosis in the early pathophysiological stages of spinal cord injury, while ephrinA1 plays a role in the nervous system’s injury response, with its reduced expression leading to impaired motor function in rats. EphA3 is upregulated following spinal cord injury, promoting an inhibitory environment for axonal regeneration. After spinal cord injury, bidirectional activation of ephrinB2 and EphB2 in astrocytes and fibroblasts results in the formation of a dense astrocyte-meningeal fibroblast scar. EphB1/ephrinB1 signaling mediates pain processing in spinal cord injury by regulating calpain-1 and caspase-3 in neurons. EphB3 expression increases in white matter after spinal cord injury, further inhibiting axon regeneration. Sema3A, expressed by neurons and fibroblasts in the scar surrounding the injury, inhibits motor neuron and sensory nerve growth after spinal cord injury. Sema4D suppresses neuronal axon myelination and axon regeneration, while its inhibition significantly enhances axon regeneration and motor recovery. Sema7A is involved in glial scar formation and may influence serotonin channel remodeling, thereby affecting motor coordination. Given these findings, the local or systemic application of neuronal guidance proteins represents a promising avenue for spinal cord injury treatment.

Key words: Eph, ephrin, Netrin-1, neuronal guidance protein, neuronal regeneration, neuronal guidance protein, SEMA3A, SEMA4D, semaphorin, Slit, spinal cord injury