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The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity
The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed pictur...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029231/ https://www.ncbi.nlm.nih.gov/pubmed/34718572 http://dx.doi.org/10.1093/hmg/ddab315 |
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author | Mason, Matthew R J van Erp, Susan Wolzak, Kim Behrens, Axel Raivich, Gennadij Verhaagen, Joost |
author_facet | Mason, Matthew R J van Erp, Susan Wolzak, Kim Behrens, Axel Raivich, Gennadij Verhaagen, Joost |
author_sort | Mason, Matthew R J |
collection | PubMed |
description | The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking. In particular, the transcriptional targets and specific functions of the various transcription factors are unclear. Jun was the first-regeneration-associated transcription factor identified and the first shown to be functionally important. Here we fully define the role of Jun in the RAG expression program in regenerating facial motor neurons. At 1, 4 and 14 days after axotomy, Jun upregulates 11, 23 and 44% of the RAG program, respectively. Jun functions relevant to regeneration include cytoskeleton production, metabolic functions and cell activation, and the downregulation of neurotransmission machinery. In silico analysis of promoter regions of Jun targets identifies stronger over-representation of AP1-like sites than CRE-like sites, although CRE sites were also over-represented in regions flanking AP1 sites. Strikingly, in motor neurons lacking Jun, an alternative SRF-dependent gene expression program is initiated after axotomy. The promoters of these newly expressed genes exhibit over-representation of CRE sites in regions near to SRF target sites. This alternative gene expression program includes plasticity-associated transcription factors and leads to an aberrant early increase in synapse density on motor neurons. Jun thus has the important function in the early phase after axotomy of pushing the injured neuron away from a plasticity response and towards a regenerative phenotype. |
format | Online Article Text |
id | pubmed-9029231 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-90292312022-04-25 The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity Mason, Matthew R J van Erp, Susan Wolzak, Kim Behrens, Axel Raivich, Gennadij Verhaagen, Joost Hum Mol Genet General Article The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking. In particular, the transcriptional targets and specific functions of the various transcription factors are unclear. Jun was the first-regeneration-associated transcription factor identified and the first shown to be functionally important. Here we fully define the role of Jun in the RAG expression program in regenerating facial motor neurons. At 1, 4 and 14 days after axotomy, Jun upregulates 11, 23 and 44% of the RAG program, respectively. Jun functions relevant to regeneration include cytoskeleton production, metabolic functions and cell activation, and the downregulation of neurotransmission machinery. In silico analysis of promoter regions of Jun targets identifies stronger over-representation of AP1-like sites than CRE-like sites, although CRE sites were also over-represented in regions flanking AP1 sites. Strikingly, in motor neurons lacking Jun, an alternative SRF-dependent gene expression program is initiated after axotomy. The promoters of these newly expressed genes exhibit over-representation of CRE sites in regions near to SRF target sites. This alternative gene expression program includes plasticity-associated transcription factors and leads to an aberrant early increase in synapse density on motor neurons. Jun thus has the important function in the early phase after axotomy of pushing the injured neuron away from a plasticity response and towards a regenerative phenotype. Oxford University Press 2021-10-28 /pmc/articles/PMC9029231/ /pubmed/34718572 http://dx.doi.org/10.1093/hmg/ddab315 Text en © The Author(s) 2021. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | General Article Mason, Matthew R J van Erp, Susan Wolzak, Kim Behrens, Axel Raivich, Gennadij Verhaagen, Joost The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity |
title | The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity |
title_full | The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity |
title_fullStr | The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity |
title_full_unstemmed | The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity |
title_short | The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity |
title_sort | jun-dependent axon regeneration gene program: jun promotes regeneration over plasticity |
topic | General Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029231/ https://www.ncbi.nlm.nih.gov/pubmed/34718572 http://dx.doi.org/10.1093/hmg/ddab315 |
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