Multiple mTOR RNA localization signals regulate subcellular protein synthesis and axonal growth

Abstract Subcellular localization of mTOR is thought to be key for regulating cell size and growth, but the relative contributions of mRNA versus protein localization are unclear. We used reporter mRNA localization assays to identify two distinct mTOR Localizing Sequences (MLS) in its 5’UTR, in addition to the localization activity already reported for the 3’UTR. Gene-edited mice with deletion of both 5’UTR MLS are mTOR hypomorphs with reduced body weight and brain size. In contrast, a mouse line lacking the second 5’UTR MLS and the 3’UTR retains near normal overall mTOR expression levels with specific subcellular perturbation of mTOR localization to neuronal axons. This subcellular mTOR deficit affects axonal local protein synthesis and neuronal growth. Thus, mTOR transcripts are localized by multiple UTR sequences, and subcellular localization of mTOR mRNA regulates local protein synthesis and neuronal growth.