title: Polycystic kidney disease in the medaka (Oryzias latipes) pc mutant caused by a mutation in the Gli-Similar3 (glis3) gene.
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.
authors.affiliation: Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan. hsshsmt@bio.nagoya-u.ac.jp
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Rieko
authors.initials: R
authors.lastname: Miyamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Dai
authors.initials: D
authors.lastname: Shiba
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ozato
authors.forename: Chikako
authors.initials: C
authors.lastname: Inoue
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kubo
authors.forename: Akihiko
authors.initials: A
authors.lastname: Koga
authors.forename: Tomoko
authors.initials: T
authors.lastname: Jindo
authors.forename: Takanori
authors.initials: T
authors.lastname: Narita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Naruse
authors.forename: Kazuko
authors.initials: K
authors.lastname: Ohishi
authors.forename: Keiko
authors.initials: K
authors.lastname: Nogata
authors.forename: Tadasu
authors.initials: T
authors.lastname: Shin-I
authors.forename: Shuichi
authors.initials: S
authors.lastname: Asakawa
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Tomotsune
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kohara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Wakamatsu
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D005456:Fluorescent Dyes; D055785:Gene Knockdown Techniques; D017403:In Situ Hybridization; D009154:Mutation; D009990:Oryzias; D010179:Pancreas / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000473:pathology; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D017931:DNA Primers; D005456:Fluorescent Dyes; D014157:Transcription Factors