Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney

Abstract

MicroRNAs (miRNAs) are a large and growing class of small, non-coding, regulatory RNAs that control gene expression predominantly at the post-transcriptional level. The production of most functional miRNAs depends on the enzymatic activity of Dicer, an RNase III class enzyme. To address the potential action of Dicer-dependent miRNAs in mammalian kidney development, we conditionally ablated Dicer function within cells of nephron lineage and the ureteric bud-derived collecting duct system. Six2Cre-mediated removal of Dicer activity from the progenitors of the nephron epithelium led to elevated apoptosis and premature termination of nephrogenesis. Thus, Dicer action is important for maintaining the viability of this critical self-renewing progenitor pool and, consequently, development of a normal nephron complement. HoxB7Cre-mediated removal of Dicer function from the ureteric bud epithelium led to the development of renal cysts. This was preceded by excessive cell proliferation and apoptosis, and accompanied by disrupted ciliogenesis within the ureteric bud epithelium. Dicer removal also disrupted branching morphogenesis with the phenotype correlating with downregulation of Wnt11 and c-Ret expression at ureteric tips. Thus Dicer, and by inference Dicer-dependent miRNA activity, have distinct regulatory roles within different components of the developing mouse kidney. Furthermore, an understanding of miRNA action may provide new insights into the etiology and pathogenesis of renal cyst-based kidney disease.

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.…”

Doğumsal Böbrek ve İdrar Yolları Anomalilerinde MicroRNA Gen Polimorfizmleri

“…At the end of these experimental models different phenotypes have emerged. Based on these different results it was reported that miRNAs played role not only in kidney development and maintaining normal kidney functions but also in the pathogenesis of kidney disease [23][24][25][26][27][28][29][30][31] . As a limitation of our study, due to small sample size our results might not reflect the actual relation between DICER gene frequency and CAKUT.…”

MiR-124 is differentially expressed in derivatives of the sympathoadrenal cell lineage and promotes neurite elongation in chromaffin cells

“…They exert their function by binding to the 3'-untranslated region of their target mRNAs and thus either induce mRNA degradation (Guo et al 2010;Hendrickson et al 2009) or inhibit translation (Mathonnet et al 2007;Thermann and Hentze 2007). Results from mice carrying conditional null mutations for dicer, an enzyme required for the cleavage of pre-miRs into mature miRs (Bernstein et al 2001), indicate the essential role of miRNAs in many cellular processes (Cuellar et al 2008;Davis et al 2011;Harris et al 2006;Harfe et al 2005;Nagalakshmi et al 2011). MicroRNAs are believed to contribute to the specification and differentiation of various cell types including neurons (Åkerblom et al 2012;Yu et al 2008;Stappert et al 2013).…”