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CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling

BACKGROUND: CNS axon regeneration inhibitors such as Nogo and CSPGs (Chondroitin Sulfate Proteoglycans) are major extrinsic factors limiting outgrowth of severed nerve fibers. However, knowledge on intracellular signaling cascades and gene expression programs activated by these inhibitors in neurons...

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Autores principales: Stern, Sina, Knöll, Bernd
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243276/
https://www.ncbi.nlm.nih.gov/pubmed/25406759
http://dx.doi.org/10.1186/s13041-014-0086-6
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author Stern, Sina
Knöll, Bernd
author_facet Stern, Sina
Knöll, Bernd
author_sort Stern, Sina
collection PubMed
description BACKGROUND: CNS axon regeneration inhibitors such as Nogo and CSPGs (Chondroitin Sulfate Proteoglycans) are major extrinsic factors limiting outgrowth of severed nerve fibers. However, knowledge on intracellular signaling cascades and gene expression programs activated by these inhibitors in neurons is sparse. Herein we studied intracellular signaling cascades activated by total myelin, Nogo and CSPGs in primary mouse CNS neurons. RESULTS: Total myelin, Nogo and CSPGs stimulated gene expression activity of the serum response factor (SRF), a central gene regulator of immediate early (IEG) and actin cytoskeletal gene transcription. As demonstrated by pharmacological interference, SRF-mediated IEG activation by myelin, Nogo or CSPGs depended on MAP kinase, to a lesser extent on Rho-GTPase but not on PKA signaling. Stimulation of neurons with all three axon growth inhibitors activated the MAP kinase ERK. In addition to ERK activation, myelin activated the IEG c-Fos, an important checkpoint of neuronal survival vs. apoptosis. Employing Srf deficient neurons revealed that myelin-induced IEG activation requires SRF. This suggests an SRF function in mediating neuronal signaling evoked by axon regeneration associated inhibitors. Besides being a signaling target of axon growth inhibitors, we show that constitutively-active SRF-VP16 can be employed to circumvent neurite growth inhibition imposed by myelin, Nogo and CSPGs. CONCLUSION: In sum, our data demonstrate that axon regeneration inhibitors such as Nogo trigger gene expression programs including an SRF-dependent IEG response via MAP kinases and Rho-GTPases.
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spelling pubmed-42432762014-11-26 CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling Stern, Sina Knöll, Bernd Mol Brain Research BACKGROUND: CNS axon regeneration inhibitors such as Nogo and CSPGs (Chondroitin Sulfate Proteoglycans) are major extrinsic factors limiting outgrowth of severed nerve fibers. However, knowledge on intracellular signaling cascades and gene expression programs activated by these inhibitors in neurons is sparse. Herein we studied intracellular signaling cascades activated by total myelin, Nogo and CSPGs in primary mouse CNS neurons. RESULTS: Total myelin, Nogo and CSPGs stimulated gene expression activity of the serum response factor (SRF), a central gene regulator of immediate early (IEG) and actin cytoskeletal gene transcription. As demonstrated by pharmacological interference, SRF-mediated IEG activation by myelin, Nogo or CSPGs depended on MAP kinase, to a lesser extent on Rho-GTPase but not on PKA signaling. Stimulation of neurons with all three axon growth inhibitors activated the MAP kinase ERK. In addition to ERK activation, myelin activated the IEG c-Fos, an important checkpoint of neuronal survival vs. apoptosis. Employing Srf deficient neurons revealed that myelin-induced IEG activation requires SRF. This suggests an SRF function in mediating neuronal signaling evoked by axon regeneration associated inhibitors. Besides being a signaling target of axon growth inhibitors, we show that constitutively-active SRF-VP16 can be employed to circumvent neurite growth inhibition imposed by myelin, Nogo and CSPGs. CONCLUSION: In sum, our data demonstrate that axon regeneration inhibitors such as Nogo trigger gene expression programs including an SRF-dependent IEG response via MAP kinases and Rho-GTPases. BioMed Central 2014-11-19 /pmc/articles/PMC4243276/ /pubmed/25406759 http://dx.doi.org/10.1186/s13041-014-0086-6 Text en © Stern and Knöll; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Stern, Sina
Knöll, Bernd
CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling
title CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling
title_full CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling
title_fullStr CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling
title_full_unstemmed CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling
title_short CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling
title_sort cns axon regeneration inhibitors stimulate an immediate early gene response via map kinase-srf signaling
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243276/
https://www.ncbi.nlm.nih.gov/pubmed/25406759
http://dx.doi.org/10.1186/s13041-014-0086-6
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