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Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function

N6‐Methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs (mRNAs) of eukaryotes and plays a vital role in post‐transcriptional regulation. Recent studies demonstrated that m6A is essential for the normal function of the central nervous system (CNS), and the deregulation...

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Autores principales: Teng, Yan, Liu, Zhihao, Chen, Xingmin, Liu, Yanzhuo, Geng, Fan, Le, Weidong, Jiang, Haisong, Yang, Lu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419180/
https://www.ncbi.nlm.nih.gov/pubmed/34288397
http://dx.doi.org/10.1111/jcmm.16740
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author Teng, Yan
Liu, Zhihao
Chen, Xingmin
Liu, Yanzhuo
Geng, Fan
Le, Weidong
Jiang, Haisong
Yang, Lu
author_facet Teng, Yan
Liu, Zhihao
Chen, Xingmin
Liu, Yanzhuo
Geng, Fan
Le, Weidong
Jiang, Haisong
Yang, Lu
author_sort Teng, Yan
collection PubMed
description N6‐Methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs (mRNAs) of eukaryotes and plays a vital role in post‐transcriptional regulation. Recent studies demonstrated that m6A is essential for the normal function of the central nervous system (CNS), and the deregulation of m6A leads to a series of CNS diseases. However, the functional consequences of m6A deficiency within the dopaminergic neurons of adult brain are elusive. To evaluate the necessity of m6A in dopaminergic neuron functions, we conditionally deleted Mettl14, one of the most important part of m6A methyltransferase complexes, in the substantia nigra (SN) region enriched with dopaminergic neurons. By using rotarod test, pole test, open‐field test and elevated plus maze, we found that the deletion of Mettl14 in the SN region induces impaired motor function and locomotor activity. Further molecular analysis revealed that Mettl14 deletion significantly reduced the total level of m6A in the mRNA isolated from SN region. Tyrosine hydroxylase (TH), an essential enzyme for dopamine synthesis, was also down‐regulated upon Mettl14 deletion, while the activation of microglia and astrocyte was enhanced. Moreover, the expression of three essential transcription factors in the regulation of TH including Nurr1, Pitx3 and En1, with abundant m6A‐binding sites on their RNA 3’‐untranslated regions (UTR), was significantly decreased upon Mettl14 deletion in SN. Our finding first confirmed the significance of m6A in maintaining normal dopaminergic function in the SN of adult mouse.
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spelling pubmed-84191802021-09-08 Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function Teng, Yan Liu, Zhihao Chen, Xingmin Liu, Yanzhuo Geng, Fan Le, Weidong Jiang, Haisong Yang, Lu J Cell Mol Med Short Communication N6‐Methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs (mRNAs) of eukaryotes and plays a vital role in post‐transcriptional regulation. Recent studies demonstrated that m6A is essential for the normal function of the central nervous system (CNS), and the deregulation of m6A leads to a series of CNS diseases. However, the functional consequences of m6A deficiency within the dopaminergic neurons of adult brain are elusive. To evaluate the necessity of m6A in dopaminergic neuron functions, we conditionally deleted Mettl14, one of the most important part of m6A methyltransferase complexes, in the substantia nigra (SN) region enriched with dopaminergic neurons. By using rotarod test, pole test, open‐field test and elevated plus maze, we found that the deletion of Mettl14 in the SN region induces impaired motor function and locomotor activity. Further molecular analysis revealed that Mettl14 deletion significantly reduced the total level of m6A in the mRNA isolated from SN region. Tyrosine hydroxylase (TH), an essential enzyme for dopamine synthesis, was also down‐regulated upon Mettl14 deletion, while the activation of microglia and astrocyte was enhanced. Moreover, the expression of three essential transcription factors in the regulation of TH including Nurr1, Pitx3 and En1, with abundant m6A‐binding sites on their RNA 3’‐untranslated regions (UTR), was significantly decreased upon Mettl14 deletion in SN. Our finding first confirmed the significance of m6A in maintaining normal dopaminergic function in the SN of adult mouse. John Wiley and Sons Inc. 2021-07-21 2021-09 /pmc/articles/PMC8419180/ /pubmed/34288397 http://dx.doi.org/10.1111/jcmm.16740 Text en © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Communication
Teng, Yan
Liu, Zhihao
Chen, Xingmin
Liu, Yanzhuo
Geng, Fan
Le, Weidong
Jiang, Haisong
Yang, Lu
Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function
title Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function
title_full Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function
title_fullStr Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function
title_full_unstemmed Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function
title_short Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function
title_sort conditional deficiency of m6a methyltransferase mettl14 in substantia nigra alters dopaminergic neuron function
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419180/
https://www.ncbi.nlm.nih.gov/pubmed/34288397
http://dx.doi.org/10.1111/jcmm.16740
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