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Neuron. 2018 Jul 25;99(2):283-292.e5. doi: 10.1016/j.neuron.2018.06.007. Epub 2018 Jun 28.

Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal Function and Learning.

Author information

1
Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.
2
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
3
Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA.
4
Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL 60637, USA.
5
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
6
Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA; Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA. Electronic address: xzhuang@uchicago.edu.

Abstract

N6-methyladenosine (m6A) regulates mRNA metabolism and translation, serving as an important source of post-transcriptional regulation. To date, the functional consequences of m6A deficiency within the adult brain have not been determined. To achieve m6A deficiency, we deleted Mettl14, an essential component of the m6A methyltransferase complex, in two related yet discrete mouse neuronal populations: striatonigral and striatopallidal. Mettl14 deletion reduced striatal m6A levels without altering cell numbers or morphology. Transcriptome-wide profiling of m6A-modified mRNAs in Mettl14-deleted striatum revealed downregulation of similar striatal mRNAs encoding neuron- and synapse-specific proteins in both neuronal types, but striatonigral and striatopallidal identity genes were uniquely downregulated in each respective manipulation. Upregulated mRNA species encoded non-neuron-specific proteins. These changes increased neuronal excitability, reduced spike frequency adaptation, and profoundly impaired striatal-mediated behaviors. Using viral-mediated, neuron-specific striatal Mettl14 deletion in adult mice, we further confirmed the significance of m6A in maintaining normal striatal function in the adult mouse.

KEYWORDS:

Mettl14; N(6)-methyladenosine; epitranscriptome; m(6)A; mRNA methylation; striatal learning; striatonigral neurons; striatopallidal neurons; translational regulation

PMID:
30056831
PMCID:
PMC6082022
[Available on 2019-07-25]
DOI:
10.1016/j.neuron.2018.06.007

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