Regulation of a multipotent spinal cord progenitor population

Abstract

Mammalian spinal cord injury is permanent due in part to a lack of local injury-induced neurogenesis. For the zebrafish, however, even complete spinal transection is temporary: the adult recovers within 6-8 weeks postinjury. We sought to create a companion model for studying regeneration after spinal cord injury (SCI) in the larval zebrafish. We have shown that recovery in the larval animal is even more rapid than in the adult: injured larvae exhibit sensory recovery within 2 days postinjury (dpi) and functional recovery by 5dpi, thereby establishing the larval zebrafish as a tractable companion model for studying regeneration after SCI. Dbx1 expression labels a transient multipotent progenitor population in the murine spinal cord. As recovery from SCI relies in part upon a resident neural progenitor population, we asked whether an analogous population might exist beyond embryogenesis in the zebrafish. We found that dbx1a-expressing cells persisted as neurogenic radial glial progenitors beyond embryogenesis and that they contribute to the neurogenic response after SCI that may be exploited for healing measures after SCI. We next asked if Wnt/β-catenin signaling might regulate SCI-induced regeneration. Using a Wnt reporter line, we found reporter expression in the blastema following injury, and that blastemal radial glia expressing the reporter were neurogenic. For further analysis, we generated a transgenic line with tamoxifen-inducible Cre activity to permanently label radial glia. During development, converted cells were quiescent spinal radial glial, nominally neurogenic. However, after SCI, converted cells proliferated in the blastema and became highly neurogenic. In the presence of IWR1, a Wnt inhibitor, converted cells showed a neurogenic delay after SCI; this delay was due to inhibited expression of proneural gene ascl1a. My work has characterized the contributions of radial glial neural progenitor cells during development and their injury-induced response during spinal cord regeneration. I've established new genetic tools and reproducible techniques for continued analysis of the mechanisms involved in spinal cord regeneration. Nature has already developed a regenerative solution to spinal cord injury; continued study of this amazing process will eventually lead to its recapitulation in regenerative medicine.