Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors

In humans, optic nerve damage caused by trauma or diseases such as glaucoma can result in permanent visual loss. The permanence of the damage is due to a failure of the human central nervous system (CNS) to support regenerative nerve growth. In contrast, fish naturally respond to optic nerve injury by re-establishing the growth capacity of CNS neurons and eventually recovering visual function. It is well known that the cellular programming regulating nerve growth and guidance in the developing visual system is highly conserved between fish and humans. Once the mature visual circuitry has been established, the cells undergo a shift in programming from one that promotes the wiring of the visual system to one that promotes the transmittal of light information, gathered in the retina, to the brain where it is perceived as an image. Thus, what appears to set fish apart from humans is their ability to reprogram adult retinal neurons for wiring in response to optic nerve injury. The goal of this study was to understand how adult retinal ganglion cells are reprogrammed for axon growth after optic nerve injury. We achieved this goal by coupling temporal analysis of gene expression with the identification of putative regulatory interactions over the full course of optic nerve regeneration in zebrafish. More specifically, we conducted a temporal analysis of gene expression (RNA-Seq) and chromatin accessibility (ATAC-Seq) over the course of optic nerve regeneration in adult zebrafish. We used time points corresponding to different stages of axon regeneration after optic nerve crush: 2 days post injury (dpi), initial axon growth past the site of injury; 4 dpi, growth across the midline; 7 dpi, target selection; 12 dpi synaptogenesis.