Loss of Larp1 disrupts the synaptic localization of TOP mRNAs and impairs spatial memory.

Post-transcriptional regulation of mRNAs allows for rapid and local control of gene expression. In vertebrates, the mTOR Complex 1 pathway post-transcriptionally controls the translation and stability of terminal oligopyrimidine motif mRNAs (TOP mRNAs), which encode ribosomal proteins and other essential factors. These mRNAs also preferentially localize to neuronal synapses, axons and dendrites, suggesting a role in growth and/or plasticity. To determine brain functions of TOP regulation, we generated mice where La-related protein 1 (Larp1), the TOP regulator downstream of mTORC1, is inactivated in neurons. These mice are viable but brain size is significantly reduced. The translation of TOP mRNAs is derepressed, but mRNA levels are depleted more than 50%. Depletion was exacerbated at synapses, reversing the enrichment observed in wild-type neurons, and accompanied by impaired spatial memory. These observations highlight the importance of post-transcriptional regulation of TOP mRNAs for brain growth and neuronal functions underlying learning and memory. Overall design: RNA was isolated from 3 Nestin-Cre male mice and 3 Nestin-Cre;Larp1-flox/flox mice and used to prepare RNA-seq libraries using the NEB Ultra II Directional RNA-seq library preparation kit.