Around 18,000 Americans suffer new spinal cord injuries (SCI) each year. Primary and secondary damages caused by SCI permanently impair sensory and motor functions, which require long-term therapeutic, rehabilitative, and psychological interventions. Thus, developing therapies to treat or reverse SCI is a pressing need in regenerative medicine. In contrast to mammals, teleost fish naturally regenerate functional neural tissue and reverse paralysis after complete spinal cord (SC) transection. Following SCI, adult zebrafish initiate a glial bridge that reconnects the severed SC, and regenerate functional neurons that contribute to SC repair. Pro-regenerative glial bridging and efficient adult neurogenesis distinguish the zebrafish SC from the mammalian SC and enable natural repair post-injury. Importantly, these pro-regenerative processes occur without the detrimental outcomes of reactive gliosis or neurotoxicity elicited by the mammalian SC. However, little is known about the cellular and molecular mechanisms that direct glial bridging or neurogenesis in zebrafish. In this proposal, we will 1) investigate the signaling pathways that direct glial bridging, 2) identify a new regulator of neurogenesis, and 3) identify the progenitor cells that give rise to bridging glia or regenerating neurons after SCI. This study will provide mechanistic understanding of glial bridging and neurogenesis during zebrafish SC regeneration, and will guide approaches for manipulating SCI outcomes in mammals.
Spinal cord injuries are devastating, incurable conditions. Unlike mammals, zebrafish possess specialized bridging cells and regenerate new neuronal cells that support natural regeneration after spinal cord injury. Our work will provide in depth understanding of cells and molecules that direct these regenerative processes in zebrafish, and will guide approaches for manipulating the burdens to mammalian spinal cord repair.
