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Sci Rep. 2019 Oct 2;9(1):14198. doi: 10.1038/s41598-019-50485-6.

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

Author information

1
Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA.
2
GABI, INRA, AgroParisTech, Universite Paris-Saclay, 78350, Jouy-en-Josas, France.
3
Joseph J Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA.
4
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
5
Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA. audvadia@uwm.edu.

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. Fish are able to undergo damage-induced "reprogramming" through re-expression of genes necessary for axon growth and guidance, however, the gene regulatory mechanisms remain unknown. Here we present the first comprehensive analysis of gene regulatory reprogramming in zebrafish retinal ganglion cells at specific time points along the axon regeneration continuum from early growth to target re-innervation. 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 (1) the beginning of regenerative axon growth in the optic nerve, and (2) 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 regulatory candidates for therapeutic development.

PMID:
31578350
DOI:
10.1038/s41598-019-50485-6
Free PMC Article

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