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hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons

Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of...

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Autores principales: Briese, Michael, Saal-Bauernschubert, Lena, Ji, Changhe, Moradi, Mehri, Ghanawi, Hanaa, Uhl, Michael, Appenzeller, Silke, Backofen, Rolf, Sendtner, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866599/
https://www.ncbi.nlm.nih.gov/pubmed/29507242
http://dx.doi.org/10.1073/pnas.1721670115
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author Briese, Michael
Saal-Bauernschubert, Lena
Ji, Changhe
Moradi, Mehri
Ghanawi, Hanaa
Uhl, Michael
Appenzeller, Silke
Backofen, Rolf
Sendtner, Michael
author_facet Briese, Michael
Saal-Bauernschubert, Lena
Ji, Changhe
Moradi, Mehri
Ghanawi, Hanaa
Uhl, Michael
Appenzeller, Silke
Backofen, Rolf
Sendtner, Michael
author_sort Briese, Michael
collection PubMed
description Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth. Here, we used individual nucleotide-resolution cross-linking and immunoprecipitation (iCLIP) to determine the RNA interactome of hnRNP R in motoneurons. We identified ∼3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the noncoding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus and also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R, and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK-deletion mutants, we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the PTEF-B complex involved in transcriptional regulation. These results propose a role for 7SK as an essential interactor of hnRNP R to regulate its function in axon maintenance.
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spelling pubmed-58665992018-03-29 hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons Briese, Michael Saal-Bauernschubert, Lena Ji, Changhe Moradi, Mehri Ghanawi, Hanaa Uhl, Michael Appenzeller, Silke Backofen, Rolf Sendtner, Michael Proc Natl Acad Sci U S A PNAS Plus Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth. Here, we used individual nucleotide-resolution cross-linking and immunoprecipitation (iCLIP) to determine the RNA interactome of hnRNP R in motoneurons. We identified ∼3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the noncoding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus and also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R, and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK-deletion mutants, we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the PTEF-B complex involved in transcriptional regulation. These results propose a role for 7SK as an essential interactor of hnRNP R to regulate its function in axon maintenance. National Academy of Sciences 2018-03-20 2018-03-05 /pmc/articles/PMC5866599/ /pubmed/29507242 http://dx.doi.org/10.1073/pnas.1721670115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Briese, Michael
Saal-Bauernschubert, Lena
Ji, Changhe
Moradi, Mehri
Ghanawi, Hanaa
Uhl, Michael
Appenzeller, Silke
Backofen, Rolf
Sendtner, Michael
hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons
title hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons
title_full hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons
title_fullStr hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons
title_full_unstemmed hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons
title_short hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons
title_sort hnrnp r and its main interactor, the noncoding rna 7sk, coregulate the axonal transcriptome of motoneurons
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866599/
https://www.ncbi.nlm.nih.gov/pubmed/29507242
http://dx.doi.org/10.1073/pnas.1721670115
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