Caspr1 silencing promotes axon regeneration in both peripheral and central nervous systems via negative regulation of neurofascin.

The regenerative capacity of the adult mammalian central nervous system is severely limited, posing a significant challenge for functional recovery after injury. To explore novel approaches to support neuronal regeneration, this study examined the role of Caspr1 as an inhibitor of axonal regeneration. Caspr1 expression was downregulated in dorsal root ganglion neurons in a rodent model of nerve injury and absent from regenerating axons, but localized to the neuronal soma membrane. Functional assays revealed that knocking down Caspr1 in cultured central and peripheral neurons using targeted siRNA significantly enhanced axon growth. Silencing Caspr1 in sensory neurons and retinal ganglion cells promoted the regeneration of sensory axons and the optic nerve, respectively. We further identified Nfasc as a key downstream mediator, and that Nfasc expression was negatively regulated by Caspr1. Taken together, these findings identify Caspr1 as a potent negative regulator of axonal regeneration and the novel Caspr1-Nfasc pathway as a promising therapeutic target for the axonal regeneration of mature neurons following injury.