title: Hedgehog Signaling Strength Is Orchestrated by the mir-310 Cluster of MicroRNAs in Response to Diet.
abstract: Since the discovery of microRNAs (miRNAs) only two decades ago, they have emerged as an essential component of the gene regulatory machinery. miRNAs have seemingly paradoxical features: a single miRNA is able to simultaneously target hundreds of genes, while its presence is mostly dispensable for animal viability under normal conditions. It is known that miRNAs act as stress response factors; however, it remains challenging to determine their relevant targets and the conditions under which they function. To address this challenge, we propose a new workflow for miRNA function analysis, by which we found that the evolutionarily young miRNA family, the mir-310s (mir-310/mir-311/mir-312/mir-313), are important regulators of Drosophila metabolic status. mir-310s-deficient animals have an abnormal diet-dependent expression profile for numerous diet-sensitive components, accumulate fats, and show various physiological defects. We found that the mir-310s simultaneously repress the production of several regulatory factors (Rab23, DHR96, and Ttk) of the evolutionarily conserved Hedgehog (Hh) pathway to sharpen dietary response. As the mir-310s expression is highly dynamic and nutrition sensitive, this signal relay model helps to explain the molecular mechanism governing quick and robust Hh signaling responses to nutritional changes. Additionally, we discovered a new component of the Hh signaling pathway in Drosophila, Rab23, which cell autonomously regulates Hh ligand trafficking in the germline stem cell niche. How organisms adjust to dietary fluctuations to sustain healthy homeostasis is an intriguing research topic. These data are the first to report that miRNAs can act as executives that transduce nutritional signals to an essential signaling pathway. This suggests miRNAs as plausible therapeutic agents that can be used in combination with low calorie and cholesterol diets to manage quick and precise tissue-specific responses to nutritional changes.
authors.affiliation: Max Planck Research Group of Gene Expression and Signaling, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Ibrahim Ömer
authors.initials: IÖ
authors.lastname: Çiçek
authors.affiliation: Bioanalytical Mass Spectrometry Research Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Samir
authors.initials: S
authors.lastname: Karaca
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Brankatschk
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eaton
authors.affiliation: Bioanalytical Mass Spectrometry Research Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Max Planck Research Group of Gene Expression and Signaling, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany halyna.shcherbata@mpibpc.mpg.de.
authors.forename: Halyna R
authors.identifier: http://orcid.org/0000-0002-3855-0345
authors.initials: HR
authors.lastname: Shcherbata
mesh_terms: D000818:Animals; D004032:Diet; D029721:Drosophila Proteins / Q000502:physiology; D004331:Drosophila melanogaster / Q000502:physiology*; D004734:Energy Metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000502:physiology*; D006706:Homeostasis; D035683:MicroRNAs / Q000502:physiology*; D010053:Ovary / Q000502:physiology; D015398:Signal Transduction; D055153:Stem Cell Niche; D033921:Vesicular Transport Proteins / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D035683:MicroRNAs; C551451:Rab23 protein, Drosophila; D033921:Vesicular Transport Proteins
keywords: Drosophila; Hedgehog signaling; Hh ligand; Rab23; dietary restriction; follicle stem cell; metabolic stress; miRNA; oogenesis; the mir-310s