Loss of Dgcr8-mediated microRNA expression in the kidney results in hydronephrosis and renal malformation

BMC Nephrol. 2015 Apr 14;16:55. doi: 10.1186/s12882-015-0053-1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation, Developmental / genetics*
  • Gene Knockout Techniques
  • Hydronephrosis / genetics*
  • Integrases
  • Kidney / abnormalities*
  • Kidney / metabolism
  • Kidney Diseases, Cystic / genetics*
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Nephrons / metabolism
  • Phenotype
  • RNA-Binding Proteins / genetics*
  • Renal Insufficiency / genetics*
  • Ribonuclease III / genetics
  • Urogenital Abnormalities / genetics*

Substances

  • Dgcr8 protein, mouse
  • MicroRNAs
  • RNA-Binding Proteins
  • Cre recombinase
  • Integrases
  • Ribonuclease III