mRNA stability and m6A are major determinants of subcellular mRNA localization in neurons

For cells to perform their biological functions, they need to adopt specific shapes and form functionally distinct subcellular compartments. This is achieved in part via an asymmetric distribution of mRNAs within cells. Currently, the main model of mRNA localization involves specific sequences called “zipcodes” that direct mRNAs to their proper locations. However, while thousands of mRNAs localize within cells, only a few zipcodes have been identified, suggesting that additional mechanisms contribute to localization. Here, we assess the role of mRNA stability in localization by combining the isolation of the soma and neurites of mouse primary cortical and mESC-derived neurons, SLAM-seq, m6A-RIP-seq, the perturbation of mRNA destabilization mechanisms, and the analysis of multiple mRNA localization datasets. We show that depletion of mRNA destabilization elements, such as m6A, AU-rich elements, and suboptimal codons, functions as a mechanism that mediates the localization of mRNAs associated with housekeeping functions to neurites in several types of neurons. [Display omitted] •Neurite-localized mRNAs are stable due to the depletion of destabilizing elements•These mRNAs are linked to housekeeping functions such as translation•m6A-linked degradation sorts mRNAs between soma and neurites•High mRNA stability is both necessary and sufficient for localization to neurites Loedige et al. revise the existing mRNA localization model, demonstrating that a high mRNA half-life in neurons reliably predicts localization to neurites. This mechanism appears essential for localizing the bulk of housekeeping mRNAs, such as those involved in translation, thus playing a key role in neuronal activity.