title: Post-developmental microRNA expression is required for normal physiology, and regulates aging in parallel to insulin/IGF-1 signaling in C. elegans.
abstract: Regulation of gene expression by microRNAs (miRNAs) is essential for normal development, but the roles of miRNAs in the physiology of adult animals are poorly understood. We have isolated a conditional allele of DGCR8/pash-1, which allows reversible and rapid inactivation of miRNA synthesis in vivo in Caenorhabditis elegans. This is a powerful new tool that allows dissection of post-developmental miRNA functions. We demonstrate that continuous synthesis of miRNAs is dispensable for cellular viability but critical for the physiology of adult animals. Loss of miRNA synthesis in the adult reduces lifespan and results in rapid aging. The insulin/IGF-1 signaling pathway is a critical determinant of lifespan, and is modulated by miRNAs. We find that although miRNA expression is required for some mechanisms of lifespan extension, it is not essential for the longevity of animals lacking insulin/IGF-1 signaling. Further, misregulated insulin/IGF-1 signaling cannot account for the reduced lifespan caused by disruption of miRNA synthesis. We show that miRNAs act in parallel with insulin/IGF-1 signaling to regulate a shared set of downstream genes important for physiological processes that determine lifespan. We conclude that coordinated transcriptional and post-transcriptional regulation of gene expression promotes longevity.
authors.affiliation: Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, The Henry Wellcome Building of Cancer and Developmental Biology, Cambridge CB2 1QN, United Kingdom.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Lehrbach
authors.forename: Cecilia
authors.initials: C
authors.lastname: Castro
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Murfitt
authors.forename: Cei
authors.initials: C
authors.lastname: Abreu-Goodger
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.forename: Eric A
authors.initials: EA
authors.lastname: Miska
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D020871:RNA Stability; D018510:RNA, Helminth / Q000235:genetics* / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013696:Temperature
chemical_list: D029742:Caenorhabditis elegans Proteins; D007328:Insulin; D035683:MicroRNAs; D018510:RNA, Helminth; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin