No abstract

No abstract

No abstract

Adult zebrafish are capable of anatomical and functional recovery following severe spinal cord injury. Axon growth, glial bridging and adult neurogenesis are hallmarks of cellular regeneration during spinal cord repair. However, the correlation between these cellular regenerative processes and functional recovery remains to be elucidated. Whereas the majority of established functional regeneration metrics measure swim capacity, we hypothesize that gait quality is more directly related to neurological health. Here, we performed a longitudinal swim tracking study for 60 individual zebrafish spanning 8 weeks of spinal cord regeneration. Multiple swim parameters as well as axonal and glial bridging were integrated. We established rostral compensation as a new gait quality metric that highly correlates with functional recovery. Tensor component analysis of longitudinal data supports a correspondence between functional recovery trajectories and neurological outcomes. Moreover, our studies predicted and validated that a subset of functional regeneration parameters measured 1 to 2 weeks post-injury is sufficient to predict the regenerative outcomes of individual animals at 8 weeks post-injury. Our findings established new functional regeneration parameters and generated a comprehensive correlative database between various functional and cellular regeneration outputs.

Spinal cord injury (SCI) causes irreversible loss of sensory and motor functions in mammals. In contrast to mammals, adult zebrafish are capable of efficient, spontaneous recovery after SCI. Whereas glial scarring and neuron loss accentuate spinal cord (SC) damage and inhibit regeneration in mammals, zebrafish are capable of pro‐regenerative glial bridging and effective adult neurogenesis post‐injury. Emerging evidence suggests that in mammals these pro‐regenerative processes are either inefficient or overshadowed by anti‐regenerative effects. We propose that developing efficient SCI treatments will require a deeper understanding of endogenous SC regenerative capacity, and that adult zebrafish present a valuable model to uncover fundamental, evolutionarily concealed mechanisms of mammalian SC regeneration. Although glial bridging and neurogenesis are hallmarks of the robust SC repair observed in zebrafish, the mechanisms that direct these processes are underexplored. Using expression profiling and genetic loss‐of‐function, we screened for and identified a suite of molecular factors and cell populations that are activated after injury and required for SC regeneration. These studies revealed that discrete lineage‐restricted niches of progenitor cells differentially contribute to glial bridging and neurogenesis after SCI in zebrafish. Using a battery of genetic and molecular tools, we identified yap‐ctgfa‐twist1a as a central glial bridging signaling axis, generated the first transcriptional profiles of zebrafish bridging glia, and elucidated glial cell injury responses at the single cell level in zebrafish. We are currently using our understanding of the bridging glial cell fate in zebrafish to perform molecular comparisons with mammalian glial cells, and to reprogram mammalian glia into scarless, pro‐regenerative scaffolds that promote SC regrowth. Taken together, our studies elucidate fundamental mechanisms that direct innate SC regeneration in zebrafish, and use natural SC regeneration as a platform to enhance mammalian SC repair at the molecular and cellular levels. Support or Funding Information We acknowledge support from NIH (R01‐NS113915), the Missouri Spinal Cord Injury/Disease Research Program, the McDonnell Center for Cellular and Molecular Neuroscience, the Institute of Clinical and Translational Sciences, and from Washington University School of Medicine to M.H.M.