Abstract

Dicer is a crucial enzyme for the maturation of miRNAs. Mutations in the Dicer gene are highly associated with Pleuro Pulmonary Blastoma-Family Dysplasia Syndrome (PPB-FDS, OMIM 601200), recently proposed to be renamed Dicer syndrome. Aside from the pulmonary phenotype (blastoma), renal nephroma and thyroid goiter are frequently part of Dicer syndrome. To investigate the renal phenotype, conditional knockout (cKO) mice for Dicer in Pax8 expressing cells were generated. Dicer cKO mice progressively develop a glomerulocystic phenotype coupled with urinary concentration impairment, proteinuria and severe renal failure. Higher cellular turnover of the parietal cells of Bowman’s capsule precedes the development of the cysts and the primary cilium progressively disappears with cyst-enlargement. Upregulation of GSK3β precedes the development of the glomerulocystic phenotype. Downregulation of β-catenin in the renal cortex and its cytosolic removal in the cells lining the cysts may be associated with observed accumulation of GSK3β. Alterations of β-catenin regulating pathways could promote cystic degeneration as in other models. Thus, miRNAs are fundamental in preserving renal morphology and function. Alteration of the GSK3β/β-catenin pathway could be a crucial mechanism linking miRNA dysregulation and the development of a glomerulocystic disease.

Highlights

  • MicroRNAs are small endogenous non-coding RNA molecules that regulate gene expression at the post-transcriptional level [1]

  • The thyroid has been extensively investigated previously [16]; here we focus on the renal phenotype, showing that miRNAs dysregulation alters the GSK3β/β-catenin pathway and induces cystogenesis in Dicer conditional knockout (cKO) mice

  • We showed that the integrity of the miRNAs system is essential to preserve the overall morphology and function of the renal corpuscles and collecting ducts in mouse kidneys

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Summary

Introduction

MicroRNAs (miRNAs) are small endogenous non-coding RNA molecules that regulate gene expression at the post-transcriptional level [1]. An RNase III-type endonuclease, is crucial for the final maturation of miRNAs, and, as part of the RNA-induced silencing complex (RISC), for targeting and regulating mRNA traslation [2,3,4]. Dicer Suppression, GSK3β/β-Catenin Pathway and Renal Cyst Development that Dicer is crucial for the proper function of renal cells [6,7] and nephron segments [8], especially during organogenesis [9]. Multiple nephron segment deletion leads to cyst development in adult mice [10]. Mutations of Dicer are critical for the development of the Pleuro Pulmonary BlastomaFamily Dysplasia Syndrome (PPB-FDS, OMIM 601200), a condition that affects children with PPB or their family members. Dicer mutations are highly associated with familiar and sporadic PPB-FDS, and the designation “Dicer Syndrome” has been proposed for this condition [11]. Renal nephroma and cystic goiter are the most frequent disorders associated with PPB, together with cystic tumors in other organs [11]

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