Primary and secondary tissue damage from spinal cord injury permanently impairs sensory and motor functions, causing irreversible paralysis. Developing therapies to treat and reverse spinal cord injury is an urgent need in regenerative medicine and remains an enormous research challenge. The path to an effective cure requires a combination of molecular, cellular, electrostimulatory, and engineering approaches, and must be guided by a deeper understanding of the inherent regenerative capacity of spinal cord tissue. Following spinal cord injury, nerve cell death and scar formation inhibit regeneration. To date, attempts to alleviate the negative effects of scarring and to support cell survival and nerve regrowth after injury have not overcome the challenges of mammalian spinal cord regeneration. By contrast with mammals, teleost zebrafish can form new neurons, regrow axons, and recover the ability to swim just 6 to 8 weeks after a paralyzing injury that completely severs the spinal cord. Importantly, these regenerative events proceed without massive scarring. Instead, following injury, specialized non-neural glia and other cells build a tissue bridge to connect the two severed ends, allowing axons to grow across the wound and reestablish crucial connections. Encouraging key mammalian cells to adopt this bridging behavior would shift the mammalian spinal cord injury response from scarring to regeneration, potentially to an extent sufficient to save tissue function. This highly desirable outcome requires an extensive understanding of the molecular signals that enable innate spinal cord regeneration. We have bioinformatically assessed datasets of transcriptome changes after spinal cord injury in zebrafish and mice, with the idea that factors preferentially induced in a successful context of regeneration would be instructive for such events. Based on the preliminary data from analysis of several new mutant and transgenic zebrafish strains, we propose to: 1) elucidate the roles of an induced and secreted factor in the regulation of spinal cord regeneration in zebrafish; and 2) define the molecular regulation and targets of this factor after spinal cord injury. Our work will provide an in-depth understanding of a key factor during spinal cord regeneration and reveal insights into its regulatory mechanisms. These discoveries will guide approaches for comprehending, and potentially manipulating, the capacity for human spinal cord regeneration.