Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal Function and Learning

Abstract

N-methyladenosine (mA) regulates mRNA metabolism and translation, serving as an important source of post-transcriptional regulation. To date, the functional consequences of mA deficiency within the adult brain have not been determined. To achieve mA deficiency, we deleted Mettl14, an essential component of the mA methyltransferase complex, in two related yet discrete mouse neuronal populations: striatonigral and striatopallidal. Mettl14 deletion reduced striatal mA levels without altering cell numbers or morphology. Transcriptome-wide profiling of mA-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 mA in maintaining normal striatal function in the adult mouse.

N6-methyladenosine modification modulate in the heat stress of sheep (Ovis aries)

“…We found that m 6 A mRNA modifications were mainly enriched in the CDS, near the stop codon, and in the 3 UTR, which is similar to the observed topological pattern of m 6 A methylation in mammals [23,34] and rice [28]. However, m 6 A modifications were also enriched near the start codons of Arabidopsis [25].…”

METTL3 regulates inflammatory pain by modulating m 6 A‐dependent pri‐miR‐365‐3p processing

“…17 Due to the important roles in the regulation of m 6 A modification, these methyltransferases and demethylases are also essential for many biological processes. 29 Furthermore, FTO in adult brain is important for fear memory and synaptic plasticity. 28 Deletion of METTL14 profoundly impaired striatal-mediated behaviors in adult mice.…”

The role of mRNA m6A methylation in the nervous system

“…METTL14 is critical for striatum function and transcriptional regulation of learning epitopes. In cell experiments, the deletion of METTL14 reduces striatum m 6 A levels without altering cell number or morphology, increases neuronal excitability and severely impaired striatal-mediated behavior [84].…”