Abstract
BackgroundSmall 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.MethodsWe 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.ResultsAnimals 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.ConclusionsHere 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0053-1) contains supplementary material, which is available to authorized users.
Highlights
IntroductionSmall 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
Small non-coding RNA molecules 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
The phenotype became apparent in the first weeks of life, several mice died during the weaning period leading to a significantly reduced number of DiGeorge syndrome critical region 8 (Dgcr8) knockout animals after weaning in comparison to the control genotypes (Additional file 1: Figure S1A)
Summary
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. The RNAse III enzyme catalyzing the maturation from pre-miRNA to mature microRNAs [2,3,4,5,6,7,8,9] This strategy revealed major defects in both tubular and glomerular development and maintenance. The loss of Dicer in derivatives of the ureteric bud and in the tubular system lead to a severe hydronephrosis coupled with cystic kidneys and loss of functional parenchyme [2,3,4,6]. These phenotypes strongly resemble congenital anomalies of the kidney and urinary tract (CAKUT) in the clinical setting. Whether this is truly due to loss of microRNAs has remained elusive since Dicer fulfills
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