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Dynamic regulation of RNA stability during Drosophila neurogenesis


High-throughput gene expression and functional genomics technologies have revolutionized the study of gene expression during development. Yet traditional genome-wide approaches fail to address complex patterns of gene expression, which include both synthesis and decay. Post-transcriptional regulation is essential for temporal and spatial control of protein expression. Although candidate studies have revealed important mechanisms of post-transcriptional regulation of gene expression via mRNA decay, there is a lack of global information on mRNA decay during development. TU-decay technology allows measurement of genome-wide mRNA decay in intact Drosophila embryos, across all tissues and specifically in the nervous system. Using this approach neural-specific decay kinetics were observed, including stabilization of transcripts encoding regulators of axonogenesis and destabilization of transcripts encoding ribosomal proteins and histones. These data also demonstrate mRNA stability is correlated to physiologic properties of mRNAs; mRNAs that are predicted to be translated within axon growth cones or dendrites have long half-lives while mRNAs encoding transcription factors that regulate neurogenesis have short half-lives. Searches for candidate cis-regulatory elements identified enrichment of the Pumilio recognition element (PRE) in mRNAs encoding regulators of neurogenesis. Decreased expression of the RNA-binding protein, Pumilio, stabilizes predicted neural mRNA targets and presence of a 3'UTR PRE is sufficient to trigger mRNA decay in the nervous system. Clustering of mRNAs by codon content reveals a bias in codon usage related to physiological function and neural-specific mRNA decay kinetics; ribosomal proteins and histones have higher fractions of optimal codons while transcriptional regulators and mRNAs predicted to be localized to synapses have lower fractions of optimal codons. In Drosophila whole embryos, codon optimality is correlated with mRNA decay, while in the nervous system, codon-mediated effects on mRNA decay are attenuated. This work demonstrates a dynamic post-transcriptional program including mRNA decay allows fine-tuning of gene expression during neural development.

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