title: Loss of Dgcr8-mediated microRNA expression in the kidney results in hydronephrosis and renal malformation.
abstract: BACKGROUND
  Small non-coding RNA molecules (miRNAs) play a pivotal role in regulating gene expression in development. miRNAs regulate key processes at the cellular level and thereby influence organismal and tissue development including kidney morphogenesis. A miRNA molecule is initially synthesized as a longer hairneedle-shaped RNA transcript and then processed through an enzymatic complex that contains the RNA-processing enzyme Drosha and its essential interactor Dgcr8. Resulting pre-miRNAs are then cleaved by Dicer. Recent data showed that loss of Dicer resulted in severe developmental kidney phenotypes. However, as Dicer has multiple miRNA-independent functions, it was not entirely clear whether the observed renal phenotypes could be exclusively attributed to a lack of miRNA expression.
  
  
  METHODS
  We analyzed the role of miRNAs in kidney development by conditional gene deletion of Dgcr8 in the developing kidney using a transgenic mouse line that expresses Cre recombinase in the distal nephron and derivatives of the ureteric bud in kidney development.
  
  
  RESULTS
  Animals with a gene deletion of Dgcr8 in these tissues developed severe hydronephrosis, kidney cysts, progressive renal failure and premature death within the first two months after birth, a phenotype strongly resembling Dicer deletion.
  
  
  CONCLUSIONS
  Here we show that conditional gene deletion of the essential miRNA-processing enzyme Dgcr8 in the developing renal tubular system results in severe developmental defects and kidney failure. These data confirm earlier findings obtained in Dicer knock-out animals and clearly illustrate the essential role of miRNAs in kidney development. The data suggests that miRNA dysregulation may play an important, yet ill-defined role in the pathogenesis of inborn defects of the genitourinary system and indicate that miRNA defects may be causative in the development of human disease.
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. malte.bartram@uk-koeln.de.
authors.forename: Malte P
authors.initials: MP
authors.lastname: Bartram
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. claudia.dafinger@uk-koeln.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dafinger
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. sandra.habbig@uk-koeln.de.|Department of Pediatrics, University of Cologne, Cologne, Germany. sandra.habbig@uk-koeln.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Habbig
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. thomas.benzing@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. thomas.benzing@uk-koeln.de.|Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. thomas.benzing@uk-koeln.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. bernhard.schermer@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. bernhard.schermer@uk-koeln.de.|Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. bernhard.schermer@uk-koeln.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. roman-ulrich.mueller@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. roman-ulrich.mueller@uk-koeln.de.|Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. roman-ulrich.mueller@uk-koeln.de.
authors.forename: Roman-Ulrich
authors.initials: RU
authors.lastname: Müller
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055786:Gene Knockout Techniques; D006869:Hydronephrosis / Q000235:genetics*; D019426:Integrases; D007668:Kidney / Q000002:abnormalities* / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009399:Nephrons / Q000378:metabolism; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics*; D051437:Renal Insufficiency / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics; D014564:Urogenital Abnormalities / Q000235:genetics*
chemical_list: C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C045073:Cre recombinase; D019426:Integrases; D043244:Ribonuclease III