title: A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila.
abstract: Messenger RNAs (mRNAs) often contain binding sites for multiple, different microRNAs (miRNAs). However, the biological significance of this feature is unclear, since such co-targeting miRNAs could function coordinately, independently, or redundantly with one another. Here, we show that two co-transcribed Drosophila miRNAs, let-7 and miR-125, non-redundantly regulate a common target, the transcription factor Chronologically Inappropriate Morphogenesis (Chinmo). We first characterize novel adult phenotypes associated with loss of both let-7 and miR-125, which are derived from a common, polycistronic transcript that also encodes a third miRNA, miR-100. Consistent with the coordinate upregulation of all three miRNAs in aging flies, these phenotypes include brain degeneration and shortened lifespan. However, transgenic rescue analysis reveal separable roles for these miRNAs: adult miR-125 but not let-7 mutant phenotypes are associated with ectopic Chinmo expression in adult brains and are suppressed by chinmo reduction. In contrast, let-7 is predominantly responsible for regulating chinmo during nervous system formation. These results indicate that let-7 and miR-125 function during two distinct stages, development and adulthood, rather than acting at the same time. These different activities are facilitated by an increased rate of processing of let-7 during development and a lower rate of decay of the accumulated miR-125 in the adult nervous system. Thus, this work not only establishes a key role for the highly conserved miR-125 in aging. It also demonstrates that two co-transcribed miRNAs function independently during distinct stages to regulate a common target, raising the possibility that such biphasic control may be a general feature of clustered miRNAs.
authors: Department of Biology, Indiana University, Bloomington, Bloomington, Indiana, United States of America.
authors: Geetanjali
authors: G
authors: Chawla
authors: Department of Biology, Indiana University, Bloomington, Bloomington, Indiana, United States of America.
authors: Padmini
authors: P
authors: Deosthale
authors: Medical Sciences Program, Indiana University, Bloomington, Bloomington, Indiana, United States of America.
authors: Sue
authors: S
authors: Childress
authors: Department of Biology, Indiana University, Bloomington, Bloomington, Indiana, United States of America.
authors: Yen-Chi
authors: YC
authors: Wu
authors: Department of Biology, Indiana University, Bloomington, Bloomington, Indiana, United States of America.
authors: Nicholas S
authors: NS
authors: Sokol
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000254:growth & development; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D008136:Longevity / Q000235:genetics*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009024:Morphogenesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009420:Nervous System / Q000254:growth & development / Q000473:pathology; D009474:Neurons / Q000378:metabolism
chemical_list: C515167:Chinmo protein, Drosophila; D029721:Drosophila Proteins; C531976:Let-7 microRNA, Drosophila; C558262:MIRN100 microRNA, Drosophila; C531977:MIRN125 microRNA, Drosophila; D035683:MicroRNAs; D009419:Nerve Tissue Proteins