Airway deficiency of specific miRNAs impairs Drosophila tracheal development and lifespan

<bold>Background:</bold> We had observed a deregulation of airway developmental pathways in a fly model of early-life cigarette smoke exposure. miRNAs are highly conserved epigenetic regulators of transcription that also respond to environmental factors. We therefore asked if miRNAs are involved in the smoke induced deregulation of developmental pathways. <bold>Methods:</bold> RNA-Seq data from larval airways exposed to cigarette smoke were categorized into specific pathways (HIPPO, BMP and EGFR). 15 miRNAs predicted to target all three pathways were selected and transgenic lines carrying sponges for single miRNAs were ordered. Airway specific knockdown (KD) was induced by using the Btl driver lines. The developmental stages were monitored. The length of trachea, the length of the airway terminal cells and the life span were measured. <bold>Results:</bold> Deletions of miRNA-10,133, 263b resulted in longer trachea in both female and male larvae, while miRNA-4, 9b, 87, 210, 375 resulted in longer trachea only in females, but not in males. miR-9c KD increased the tracheal length in females, but shortened in males. KD of miRNA-4 reduced length of tracheal terminal cells in males, but not in females. miRNA-4, 9b deletion shortened animals’ lifespan in males but increased in females, and miRNA-10, 87 deletion resulted in shorter lifespan in females and no difference in males. <bold>Conclusion & Outlook:</bold> The deficiency of distinct miRNAs in airway affect a larval tracheal development and lifespan in a highly sex-specific manner and will next test how these miRNAs affect physiological parameters. We will further analyze by mRNASeq which predicted mRNA-targets within HIPPO, BMP and EGFR are indeed regulated upon deficiency of our candidate miRNAs.