m(6)A and YTHDF proteins contribute to the localization of select neuronal mRNAs

The transport of mRNAs to distal subcellular compartments is an important component of spatial gene expression control in neurons. However, the mechanisms that control mRNA localization in neurons are not completely understood. Here, we identify the abundant base modification, m(6)A, as a novel regulator of this process. Transcriptome-wide analysis following genetic loss of m(6)A reveals hundreds of transcripts that exhibit altered subcellular localization in hippocampal neurons. Additionally, using a reporter system, we show that mutation of specific m(6)A sites in select neuronal transcripts diminishes their localization to neurites. Single molecule fluorescent in situ hybridization experiments further confirm our findings and identify the m(6)A reader proteins YTHDF2 and YTHDF3 as mediators of this effect. Our findings reveal a novel function for m(6)A in controlling mRNA localization in neurons and enable a better understanding of the mechanisms through which m(6)A influences gene expression in the brain.