Transfer RNA levels are tuned to support differentiation during Drosophila neurogenesis

Neural differentiation requires a multifaceted program to alter gene expression along the proliferation to differentiation axis. While critical changes occur at the level of transcription, post-transcriptional mechanisms allow fine-tuning of protein output. We investigated the role of tRNAs in regulating gene expression during neural differentiation by quantifying tRNA abundance in neural progenitor-biased and neuron-biased Drosophila larval brains. We found that tRNA profiles are largely consistent between progenitor-biased and neuron-biased brains but significant variation occurs for 10 cytoplasmic isodecoders (individual tRNA genes) and this establishes differential tRNA levels for 8 anticodon groups. We used these tRNA data to investigate relationships between tRNA abundance, codon optimality- mediated mRNA decay, and translation efficiency in progenitors and neurons. Our data reveal that tRNA levels strongly correlate with codon optimality-mediated mRNA decay within each cell type but generally do not explain differences in stabilizing versus destabilizing codons between cell types. Regarding translation efficiency, we found that tRNA expression in neural progenitors preferentially supports translation of mRNAs whose products are in high demand in progenitors, such as those associated with protein synthesis. In neurons, tRNA expression shifts to disfavor translation of proliferation-related transcripts and preferentially support translation of transcripts tied to neuron-specific functions like axon pathfinding and synapse formation. Overall, our analyses reveal that changes in tRNA levels along the neural differentiation axis support optimal gene expression in progenitors and neurons. AUTHOR SUMMARYWint et al. quantified tRNA expression in Drosophila larval brains, using wildtype brains composed primarily of neurons and mutant brains composed primarily of neural progenitors (neuroblasts). These neuron-biased and neuroblast-biased tRNA measurements, combined with mRNA decay data and computational modeling of translation efficiency, revealed that: 1) tRNA abundance is largely constant between neural progenitors and neurons but significant variation exists for 10 nuclear tRNA genes and 8 corresponding anticodon groups, 2) tRNA abundance correlates with codon-mediated mRNA decay in neuroblasts and neurons but does not completely explain the different stabilizing or destabilizing effects of certain codons, and 3) changes in tRNA levels during differentiation shift translation optimization from a program supporting proliferation to a program supporting differentiation. These findings reveal coordination between tRNA expression and codon usage in transcripts that regulate neural development.