eIF4G2 cross-linking immunoprecipitation (CLIP) in primary cortical neurons

Learning and memory require activity-induced changes in mRNA translation within dendrites, but which mRNAs are involved and how they are regulated remain unclear. We combined proximity labeling with ribosome profiling and CLIP to monitor how depolarization impacts dendritic translation. For a functionally coherent set of transcripts highly enriched in mitochondrial genes, depolarization leads to enhanced uORF translation, eIF4G2 binding, and increased translation. Engineered reporters demonstrate that activity-dependent translational control is conferred by the 5’UTRs and that dendritic localization, eIF4G2 binding, and uORF translation are necessary and sufficient to mediate this regulation. Downstream, this drives activity-dependent changes in dendritic mitochondrial function. Our studies uncover an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 enables the coupling of synaptic activity to local remodeling of dendrites.