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

Abstract : In contrast to mammals, adult fish display a remarkable ability to fully regenerate central nervous system (CNS) axons, enabling functional recovery from CNS injury. Both fish and mammals normally undergo a developmental downregulation of axon growth activity as neurons mature. However, fish spontaneously undergo damage-induced “reprogramming” through re-expression of genes necessary for axon growth, guidance, and restoration of functional synaptic connections with target neurons. What remains unknown are the gene regulatory mechanisms that underlie successful reprogramming of adult neurons for functional CNS axon regeneration. Here we present the first comprehensive analysis of gene expression changes (RNA-seq) and DNA regulatory element accessibility (ATAC-seq) in zebrafish retinal ganglion cells (RGCs) at specific time points along the axon regeneration continuum from early growth to target reinnervation. Our analyses reveal a regeneration program characterized by sequential activation of stage-specific pathways, regulated by a temporally changing cast of transcription factors that bind to stably accessible DNA regulatory regions. Strikingly, we also find a discrete set of regulatory regions that change in accessibility, consistent with higher-order changes in chromatin organization that mark (a) the beginning of regenerative axon growth in the optic nerve, and (b) the re-establishment of synaptic connections in the brain. Together, these data provide valuable insight into the regulatory logic driving successful vertebrate CNS axon regeneration, revealing key gene and gene regulatory candidates for therapeutic development. Significance statement CNS axon damage, due to acute nerve injury or degenerative diseases, often leads to permanent loss of function in human patients. Despite recent discoveries of pathways that promote or inhibit regenerative nerve growth in the mammalian CNS, the capacity for restoring neuronal connections between the retina and the brain after optic nerve damage in mammals remains elusive. Unlike mammals, optic nerve injury in fish induces the re-expression of developmentally downregulated genes that encode proteins important for re-growing and re-establishing axonal connections between the retina and the brain. These studies reveal stage-specific gene regulatory mechanisms associated with regenerating RGCs as they reinitiate axon growth, cross the midline, select appropriate brain targets, and re-establish synapses.
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Contributor : Migration Prodinra <>
Submitted on : Friday, June 5, 2020 - 8:09:57 AM
Last modification on : Wednesday, May 12, 2021 - 3:43:09 AM

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Sumona Dhara, Andrea Rau, Michael J. Flister, Nicole M. Recka, Michael D. Laiosa, et al.. Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors. Scientific Reports, Nature Publishing Group, 2019, ⟨10.1038/s41598-019-50485-6⟩. ⟨hal-02791772⟩



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