Summary: The transcriptome analysis of injured Xenopus laevis tadpole and mice suggested that Neurod4L.S., a basic-helix-loop-helix transcription factor, was the most promising transcription factor to exert neuroregeneration after spinal cord injury (SCI) in mammals. We generated a pseudotyped retroviral vector with the neurotropic lymphocytic choriomeningitis virus (LCMV) envelope to deliver murine Neurod4 to mice undergoing SCI. SCI induced ependymal cells to neural stem cells (NSCs) in the central canal. The LCMV envelope-based pseudotypedvector preferentially introduced Neurod4 into activated NSCs, which converted to neurons with axonal regrowth and suppressed the scar-forming glial lineage. Neurod4-induced inhibitory neurons predominantly projected to the subsynaptic domains of motor neurons at the epicenter, and Neurod4-induced excitatory neurons predominantly projected to subsynaptic domains of motor neurons caudal to the injury site suggesting the formation of functional synapses. Thus, Neurod4 is a potential therapeutic factor that can improve anatomical and functional recovery after SCI.
