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Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors. Sci Rep 2019 Oct 02;9(1):14198

Date

10/04/2019

Pubmed ID

31578350

Pubmed Central ID

PMC6775158

DOI

10.1038/s41598-019-50485-6

Scopus ID

2-s2.0-85072935847 (requires institutional sign-in at Scopus site)   28 Citations

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.

Author List

Dhara SP, Rau A, Flister MJ, Recka NM, Laiosa MD, Auer PL, Udvadia AJ

Authors

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Ava Udvadia BS,PhD Associate Professor in the Biological Sciences department at University of Wisconsin - Milwaukee




MESH terms used to index this publication - Major topics in bold

Animals
Axons
Cellular Reprogramming
Central Nervous System
Humans
Nerve Regeneration
Optic Nerve
Optic Nerve Injuries
Recovery of Function
Retinal Ganglion Cells
Transcription Factors
Zebrafish