title: Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.
abstract: Megalin/LRP2 is an endocytic receptor in the proximal tubules of the mammalian kidney that plays a central role in the clearance of metabolites from the glomerular filtrate. To establish a genetic model system for elucidation of molecular components of this retrieval pathway, we characterized orthologous transport processes in the zebrafish. We show that expression of megalin/LRP2 and its co-receptor cubilin is conserved in the larval zebrafish pronephros and demarcates a segment of the pronephric duct that is active in clearance of tracer from the ultrafiltrate. Knock-down of megalin/LRP2 causes lack of Rab4-positive endosomes in the proximal pronephric duct epithelium and abrogates apical endocytosis. Similarly, knock-down of the megalin/LRP2 adaptor Disabled 2 also blocks renal clearance processes. These results demonstrate the conservation of the megalin/LRP2 retrieval pathway between the larval zebrafish pronephros and the mammalian kidney and set the stage for dissection of the renal endocytic machinery in a simple model organism. Using this model system, we provide first genetic evidence that renal tubular endocytosis and formation of endosomes is a ligand-induced process that crucially depends on megalin/LRP2 activity.
authors.affiliation: Max Delbrueck Center (MDC) for Molecular Medicine, Robert-Roessle Str. 10, 13125 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Anzenberger
authors.forename: Nana
authors.initials: N
authors.lastname: Bit-Avragim
authors.forename: Stefan
authors.initials: S
authors.lastname: Rohr
authors.forename: Franziska
authors.initials: F
authors.lastname: Rudolph
authors.forename: Bastian
authors.initials: B
authors.lastname: Dehmel
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.forename: Salim
authors.initials: S
authors.lastname: Abdelilah-Seyfried
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D004705:Endocytosis; D007668:Kidney / Q000098:blood supply / Q000196:embryology* / Q000378:metabolism*; D007814:Larva; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008969:Molecular Sequence Data; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D026561:Low Density Lipoprotein Receptor-Related Protein-2