title: The Lowe syndrome protein OCRL1 is required for endocytosis in the zebrafish pronephric tubule.
abstract: Lowe syndrome and Dent-2 disease are caused by mutation of the inositol 5-phosphatase OCRL1. Despite our increased understanding of the cellular functions of OCRL1, the underlying basis for the renal tubulopathy seen in both human disorders, of which a hallmark is low molecular weight proteinuria, is currently unknown. Here, we show that deficiency in OCRL1 causes a defect in endocytosis in the zebrafish pronephric tubule, a model for the mammalian renal tubule. This coincides with a reduction in levels of the scavenger receptor megalin and its accumulation in endocytic compartments, consistent with reduced recycling within the endocytic pathway. We also observe reduced numbers of early endocytic compartments and enlarged vacuolar endosomes in the sub-apical region of pronephric cells. Cell polarity within the pronephric tubule is unaffected in mutant embryos. The OCRL1-deficient embryos exhibit a mild ciliogenesis defect, but this cannot account for the observed impairment of endocytosis. Catalytic activity of OCRL1 is required for renal tubular endocytosis and the endocytic defect can be rescued by suppression of PIP5K. These results indicate for the first time that OCRL1 is required for endocytic trafficking in vivo, and strongly support the hypothesis that endocytic defects are responsible for the renal tubulopathy in Lowe syndrome and Dent-2 disease. Moreover, our results reveal PIP5K as a potential therapeutic target for Lowe syndrome and Dent-2 disease.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Oltrabella
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Pietka
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Irene Barinaga-Rementeria
authors.initials: IB
authors.lastname: Ramirez
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Mironov
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Toby
authors.initials: T
authors.lastname: Starborg
authors.affiliation: Nephrology Division, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Drummond
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hinchliffe
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Lowe
mesh_terms: D000818:Animals; D016764:Cell Polarity; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D017353:Gene Deletion; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism; D009800:Oculocerebrorenal Syndrome / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D060910:Pronephros / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D029961:Zebrafish Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D010744:Phosphoric Monoester Hydrolases; C576582:ocrl protein, zebrafish
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