Abstract
Polycystic kidney disease (PKD) is a common hereditary disease in humans. Recent studies have shown an increasing number of ciliary genes that are involved in the pathogenesis of PKD. In this study, the Gli-similar3 (glis3) gene was identified as the causal gene of the medaka pc mutant, a model of PKD. In the pc mutant, a transposon was found to be inserted into the fourth intron of the pc/glis3 gene, causing aberrant splicing of the pc/glis3 mRNA and thus a putatively truncated protein with a defective zinc finger domain. pc/glis3 mRNA is expressed in the epithelial cells of the renal tubules and ducts of the pronephros and mesonephros, and also in the pancreas. Antisense oligonucleotide-mediated knockdown of pc/glis3 resulted in cyst formation in the pronephric tubules of medaka fry. Although three other glis family members, glis1a, glis1b and glis2, were found in the medaka genome, none were expressed in the embryonic or larval kidney. In the pc mutant, the urine flow rate in the pronephros was significantly reduced, which was considered to be a direct cause of renal cyst formation. The cilia on the surface of the renal tubular epithelium were significantly shorter in the pc mutant than in wild-type, suggesting that shortened cilia resulted in a decrease in driving force and, in turn, a reduction in urine flow rate. Most importantly, EGFP-tagged pc/glis3 protein localized in primary cilia as well as in the nucleus when expressed in mouse renal epithelial cells, indicating a strong connection between pc/glis3 and ciliary function. Unlike human patients with GLIS3 mutations, the medaka pc mutant shows none of the symptoms of a pancreatic phenotype, such as impaired insulin expression and/or diabetes, suggesting that the pc mutant may be suitable for use as a kidney-specific model for human GLIS3 patients.
Highlights
Polycystic kidney disease (PKD) is a common heritable kidney condition in humans
A putative role for pc/glis3 in PKD pathogenesis In this study, we have shown that a mutation in pc/glis3 causes
PKD in medaka (Fig. 1). pc/glis3 is continuously expressed in the ciliated epithelial cells of the renal tubule and duct during pronephric and mesonephric development (Fig. 2), and knockdown of pc/glis3 leads to dilation of the pronephric tubules (Fig. 3)
Summary
Polycystic kidney disease (PKD) is a common heritable kidney condition in humans. It is characterized by the appearance of fluid-filled cysts in the renal tubules and collecting ducts of the kidney, with pleiotropic lesions sometimes occurring in other organs, such as the liver, the retina and the pancreas (reviewed in [1]). Recent studies have proposed that renal cilia, which are immotile organelles projecting from the renal epithelium into the lumen of the nephric tubule or duct, play a crucial role in cyst formation. Animal models such as Tg737orpk and Kif3a mutant mice, which have atypically structured cilia in the renal tubule, have cystic kidneys (reviewed in [2]), suggesting that normally structured renal cilia are required for the maintenance of tubular lumen morphology. Previous reports have suggested that PKD pathogenesis is associated with aberrant cell proliferation as well as altered planar cell polarity in the renal tubular and ductal epithelium [2,9,10,11,12]
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