LINGO-1 promotes axonal regeneration and functional recovery after spinal cord injury

Abstract

Myelin inhibitory molecules prevent axonal regeneration after CNS injury. LINGO-1 is a nervous system-specific transmembrane protein that binds the Nogo-66 receptor/p75 signaling complex and is required for the inhibitory effects of myelin (Sha Mi et. al. 2004 Nature Neuroscience). Exogenously added LINGO-1-Fc fusion protein attenuates myelin inhibition in primary neuronal cultures. We examined whether LINGO-1-Fc promotes axonal regeneration of rubrospinal tract (RST) neurons and recovery of forelimb function after spinal cord injury in adult rats. The animals received a unilateral hemisection at the C7 spinal cord. Four weeks after the lesion, regeneration of RST axons was examined by injection of Fluoro-Gold at spinal level T2. The recovery of motor function was studied on a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury. Application of LINGO-Fc at the injury site promoted the regeneration of RST axons. Animals receiving the LINGO-Fc treatment used both forelimbs together more often than animals received PBS or control protein treatment. Treatment with the same amount of control protein did not promote axonal regeneration of RST and functional recovery. These results provide in vivo evidence that LINGO-1-Fc fusion protein can reverse the inhibitory activities of myelin on axonal regeneration in the injured spinal cord. LINGO-1-Fc fusion protein is a potential candidate for the therapeutic treatment of spinal cord injury.