Selective dicer suppression in the kidney alters GSK3β/β-catenin pathways promoting a glomerulocystic disease

Area of Science:

• Developmental Biology
• Genetics
• Nephrology

Background:

• Dicer enzyme is critical for microRNA maturation.
• Dicer gene mutations are linked to Pleuro Pulmonary Blastoma-Family Dysplasia Syndrome (PPB-FDS), also known as Dicer syndrome.
• Dicer syndrome presents with pulmonary, renal, and thyroid abnormalities.

Purpose of the Study:

• To investigate the renal phenotype associated with Dicer syndrome.
• To elucidate the role of Dicer and microRNAs in kidney development and function.

Main Methods:

• Generation of conditional knockout (cKO) mice lacking Dicer in Pax8-expressing cells.
• Analysis of renal morphology, function, and cellular changes in Dicer cKO mice.
• Investigation of molecular pathways, including GSK3β and β-catenin signaling.

Main Results:

• Dicer cKO mice developed a progressive glomerulocystic phenotype, impaired urinary concentration, proteinuria, and renal failure.
• Increased parietal cell turnover and primary cilium loss were observed preceding cyst development.
• Upregulation of GSK3β and downregulation of β-catenin were associated with the glomerulocystic phenotype.

Conclusions:

• MicroRNAs are fundamental for maintaining renal morphology and function.
• Disruption of the GSK3β/β-catenin pathway is a key mechanism linking microRNA dysregulation to glomerulocystic disease.
• Conditional Dicer deletion in renal cells recapitulates key features of Dicer syndrome, highlighting the importance of microRNAs in kidney homeostasis.