Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish

Abstract

Unlike mammals, zebrafish efficiently regenerate functional nervous system tissue after major spinal cord injury. Whereas glial scarring presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish form a bridge across severed spinal cord tissue and facilitate regeneration, a relatively unexplored process. Here, we performed a genome-wide profiling screen for secreted factors that are upregulated during zebrafish spinal cord regeneration. We find that connective tissue growth factor a (ctgfa) is induced in and around glial cells that participate in initial bridging events. Mutations in ctgfa disrupt spinal cord repair, while transgenic ctgfa overexpression and local human CTGF recombinant protein delivery accelerate bridging and functional regeneration. Our study reveals that CTGF is necessary and sufficient to stimulate glial bridging and natural spinal cord regeneration.

Long-term reconstruction of foveal microstructure and visual acuity after idiopathic macular hole repair: three-year follow-up study

“…In cases involving central nervous system trauma such as spinal cord injury, the repair is initiated by bridging of glial cells followed by further axon regeneration 28. In that study, local delivery of connective tissue growth factor (CTGF) protein increased the bridging activity of glial cells whereas decreased CTGF resulted in deficits in glial bridging and inhibited spinal cord regeneration.…”

Wnt signaling regulates proliferation and differentiation of radial glia in regenerative processes after stab injury in the optic tectum of adult zebrafish

“…M€ uller glia, expressing similar properties to RG in the retina, also function as neural stem cells in regenerative conditions but not in physiological adult neurogenesis conditions (Ramachandran et al, 2010;Raymond, Barthel, Bernardos, & Perkowski, 2006). However, RG in the telencephalon, hypothalamus and spinal cord of adult zebrafish function as neural stem cells in both adult and regenerative neurogenesis (Adolf et al, 2006;Gorsuch et al, 2014;Hui, Nag, and Ghosh, 2015;Johnson et al, 2016;Kishimoto et al, 2012;Kizil et al, 2012;Kroehne, Freudenreich, Hans, Kaslin, and Brand, 2011;Mokalled et al, 2016;Raymond et al, 2006). Moreover, in the cerebellum, NE, but not RG, operate as neural stem cells in both physiological and regenerative conditions (Bae et al, 2009;Kaslin, Kroehne, Ganz, Hans, & Brand, 2017).…”

Regeneration Genetics

“…Interestingly, upon tail amputation in adult animals, spinal cord regeneration was affected, supporting a preferential role during regeneration. Similarly, mutations in the extracellular ctgfa allow zebrafish to develop grossly normally to adulthood, but block regeneration of the spinal cord after it is severed (76). Mutant phenotypes for fgf20a , Sox2 , and ctgfa are consistent with the idea that some genes might be evolutionally preserved in certain species for their roles in adult tissue regeneration (29; 133).…”