UC Merced

Systems biology takes an integrative approach to connecting molecular-level mechanisms to cellular physiology and developmental outcomes. In metazoans, cellular development converges onto either a proliferative or differentiated state. Precise spatiotemporal regulation of gene expression is paramount for defining cellular proliferation and differentiation programs. During gene expression, the genetic information stored in a segment of DNA is copied into a messenger RNA (mRNA). This “message” within the mRNA is organized as a sequence of discrete units called codons. Each mRNA codon is then translated by its complementary transfer RNA (tRNA) molecule into a protein, the molecules that ultimately shape the cellular identity and function. Recently, codon identity emerged as a key regulatory grammar for post-transcriptional control of animal gene expression. Prior work from my laboratory in Drosophila demonstrated that certain “optimal” codons enhanced the stability of mRNAs in embryonic tissue, but the stabilizing effect of these codons was attenuated in the differentiated embryonic neural tissue. Current models suggest that optimal codons – codons that are enriched in high expressed and/or stable mRNAs – are preferentially decoded by abundant tRNAs. tRNAs are the adaptor molecules of mRNA translation. Mounting evidence from genomics experiments now overrides the longstanding view of tRNAs as uniformly expressed housekeeping molecules. However, genome-wide tRNA measurements, especially in vivo data, are usually missing from codon optimality studies in metazoans. Hence, our understanding of tRNA regulation in normal tissue development remains fragmentary. The Drosophila larval central nervous system offers a tractable model for studying the genetic control of cell proliferation and differentiation because of the suite of available genetic tools that enables cell type-specific assays. Here I demonstrate how altered tRNA expression establishes cell-type specific codon optimality that dynamic programs of mRNA decay and translation efficiency in neurogenesis, using the Drosophila melanogaster central nervous system. By quantifying the tRNA transcriptome, mRNA transcriptome, and mRNA degradome in neural progenitor and post-mitotic neurons, for the first time, I present evidence that supports the dynamic regulation of the tRNA levels and post-transcriptional modification across neural differentiation serves as a mechanism for coordinating the translation and stability of functionally related mRNAs in a codon-dependent manner. Collectively, these findings support a mechanistic link between translational control by tRNA and neural differentiation. Thus my work lays the foundation for future investigations of dynamic tRNA regulation in cell-fate determination in other tissue types as well as in other complex animal models.