The promiscuous low affinity neurotrophin co-receptor p75NTR, a member of the nerve tumor necrosis factor (TNF) receptor superfamily, mediates neuronal survival as well as death, and interacts with Trk receptors to increase their affinity for neurotrophins. Furthermore, p75NTR is the transmembrane signalling moiety which associates with the NOGO binding receptor for all CNC myelin-derived axon growth inhibitors in the injured CNS. We have shown in rats that intravitreal implantation of a neurotrophin secreting peripheral nerve segment promotes retinal ganglion cell (RGC) axon regeneration through the inhibitory environment of the optic nerve (ON), lesion site, and through the distal ON segment. We investigated whether 'receptor shedding' of p75NTR could contribute to the promotion of RGC axon regeneration by attenuation of Rho-A inhibitory signalling. Levels of p75NTR, detected by Western blotting, were decreased significantly in the retinae of regenerating versus non-regenerating animals with the accumulation of 55 and 25 kDa fragments of p75NTR. Additionally, retinal levels of Rho-A, which signal growth cone collapse, was significantly reduced in regenerating ON. Western blotting for candidate sheddases, ADAM-10 and -17, showed that both were highly up-regulated in the regenerating compared to the non-regenerating ON, suggesting that receptor shedding might disinhibit axon growth in the regenerating ON. Using short interference RNA (siRNA) to p75NTR to specifically knock down the expression of p75NTR, we showed that the 75, 55 and 25 kDa fragment were knocked out in RGC in vitro, with significant promotion of TRk-independent CNTF driven RGC neurite outgrowth, in the presence of inhibitory CNS myelin. siRNA-mediated knockdown of p75NTR also led to the complete knockdown of Rho-A. These results suggest that neurotrophin-induced down-regulation of p75NTR, via ADAM-mediated receptor shedding, may disinhibit RGC axon growth thereby enhancing regeneration through the putative inhibitory environment of the ON.