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Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors
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 unde...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775158/ https://www.ncbi.nlm.nih.gov/pubmed/31578350 http://dx.doi.org/10.1038/s41598-019-50485-6 |
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author | Dhara, Sumona P. Rau, Andrea Flister, Michael J. Recka, Nicole M. Laiosa, Michael D. Auer, Paul L. Udvadia, Ava J. |
author_facet | Dhara, Sumona P. Rau, Andrea Flister, Michael J. Recka, Nicole M. Laiosa, Michael D. Auer, Paul L. Udvadia, Ava J. |
author_sort | Dhara, Sumona P. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6775158 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67751582019-10-09 Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors Dhara, Sumona P. Rau, Andrea Flister, Michael J. Recka, Nicole M. Laiosa, Michael D. Auer, Paul L. Udvadia, Ava J. Sci Rep Article 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. Nature Publishing Group UK 2019-10-02 /pmc/articles/PMC6775158/ /pubmed/31578350 http://dx.doi.org/10.1038/s41598-019-50485-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dhara, Sumona P. Rau, Andrea Flister, Michael J. Recka, Nicole M. Laiosa, Michael D. Auer, Paul L. Udvadia, Ava J. Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors |
title | Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors |
title_full | Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors |
title_fullStr | Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors |
title_full_unstemmed | Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors |
title_short | Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors |
title_sort | cellular reprogramming for successful cns axon regeneration is driven by a temporally changing cast of transcription factors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775158/ https://www.ncbi.nlm.nih.gov/pubmed/31578350 http://dx.doi.org/10.1038/s41598-019-50485-6 |
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