TY - JOUR
T1 - Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function
AU - Teng, Yan
AU - Liu, Zhihao
AU - Chen, Xingmin
AU - Liu, Yanzhuo
AU - Geng, Fan
AU - Le, Weidong
AU - Jiang, Haisong
AU - Yang, Lu
N1 - Funding Information:
The authors would like to thank Dr Li Hua‐bing (Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, School of Medicine, Shanghai Jiao Tong University) for his support to provide us the Mettl14‐loxp mice. This work was supported by funding from the National Natural Science Foundation of China (81601125) and Central University Basic Scientific Research Business Expenses Special Funds (A03019023801206).
Funding Information:
The authors would like to thank Dr Li Hua-bing (Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, School of Medicine, Shanghai Jiao Tong University) for his support to provide us the Mettl14-loxp mice. This work was supported by funding from the National Natural Science Foundation of China (81601125) and Central University Basic Scientific Research Business Expenses Special Funds (A03019023801206).
Publisher Copyright:
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Mettl14
KW - dopaminergic neuron
KW - m6A
KW - tyrosine hydroxylase
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U2 - 10.1111/jcmm.16740
DO - 10.1111/jcmm.16740
M3 - Article
C2 - 34288397
AN - SCOPUS:85110986900
SN - 1582-1838
VL - 25
SP - 8567
EP - 8572
JO - Journal of Cellular and Molecular Medicine
JF - Journal of Cellular and Molecular Medicine
IS - 17
ER -