Genetic analyses reveal a requirement for Dicer1 in the mouse urogenital tract

Abstract

Despite the increasing interest in other classes of small RNAs, microRNAs (miRNAs) remain the most widely investigated and have been shown to play a role in a number of different processes in mammals. Many studies investigating miRNA function focus on the processing enzyme Dicer1, which is an RNAseIII protein essential for the biogenesis of active miRNAs through its cleavage of precursor RNA molecules. General deletion of Dicer1 in the mouse confirms that miRNAs are essential for development because embryos lacking Dicer1 fail to reach the end of gastrulation. Here we investigate the role of Dicer1 in urogenital tract development. We utilised a conditional allele of the Dicer1 gene and two Cre-expressing lines, driven by HoxB7 and Amhr2, to investigate the effect of Dicer1 deletion on both male and female reproductive tract development. Data presented here highlight an essential role for Dicer1 in the correct morphogenesis and function of the female reproductive tract and confirm recent findings that suggest Dicer1 is required for female fertility. In addition, HoxB7:Cre-mediated deletion in ureteric bud derivatives leads to a spectrum of anomalies in both males and females, including hydronephrotic kidneys and kidney parenchymal cysts. Male reproductive tract development, however, remains largely unaffected in the absence of Dicer1. Thus, Dicer1 is required for development of the female reproductive tract and also normal kidney morphogenesis.

Regulation of WNK1 Expression by miR-192 and Aldosterone

“…9 Deletion of Dicer in various compartments of the kidney demonstrated the requirement of miRs in the establishment of renal structure and podocyte function. 10 We describe here that, in addition to an already complex transcriptional regulation, the expression of WNK1 is likely to be regulated at the post-transcriptional level by miR-192, a miR expressed only in the kidney and the gastrointestinal tract. 6 We also show that the expression of miR-192 is regulated by sodium/potassium intake and aldosterone in the kidney, in a way opposite to WNK1 isoforms.…”

“…miR-192 has been implicated in the development of diabetic nephropathy. 9 The inactivation of Dicer in developing renal structures 10 or in podocytes 11,12 demonstrated a requirement for miRs in kidney development and in the maintenance of podocyte structure and functions.…”

Small RNAs Have a Big Effect on Polycystic Kidney Disease

“…In this study, mice lacking Dicer in kidney tubules and collecting ducts exhibit hydronephrosis, hydroureter, and cyst formation. 8 Although a similar phenotype was reported previously, 6,7 Patel et al further extend their analysis to mechanistically explain the phenotype. 8 Small RNA profiling identified multiple miRNAs downregulated in Dicer mutant kidneys.…”

“…2 Thus, it is very surprising that in one of the most abundant human diseases, polycystic kidney disease (PKD), miRNAs have thus far only been implicated intermittently and direct mechanistic data are scarce. [3][4][5][6][7] The article by Patel et al in this issue of JASN now demonstrates a direct link between cyst formation, miRNAs, and Polycystin-1, the gene most frequently mutated in human autosomal dominant PKD (ADPKD). 8 Patel et al used one of the most fruitful approaches to explore the role of miRNAs in organogenesis-the conditional ablation of Dicer, a key enzyme in miRNA biogenesis.…”

MicroARN et maladies rénales

“…La technique d'invalidation conditionnelle a donc été utilisée ensuite pour évaluer l'implication des miARN au cours du développement des différents types cellulaires, notamment de l'appareil urinaire. L'invalidation de Dicer dans le bourgeon urétéral chez la souris conduit à l'apparition de microkystes tubulaires et d'une hydronéphrose dès trois semaines de développement, ce qui confirme le rôle des miARN dans le développement de l'épithélium du tube collecteur et de l'urothélium [7]. Chez des souris mutantes caractérisées par une délétion conditionnelle de Dicer dans les cellules juxta-glomérulaires sécrétrices de rénine, Sequeira-Lopez et al [8] ont observé une diminution du nombre de ces cellules associée à une diminution de l'expression des gènes Renin1 et Renin2 et de la concentration plasmatique de rénine, ainsi qu'une baisse de la pression artérielle de 10 mmHg.…”