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First published online 25 April 2006
doi: 10.1242/jcs.02954

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Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros

¹ Max Delbrueck Center (MDC) for Molecular Medicine, Robert-Roessle Str. 10, 13125 Berlin, Germany
² Department of Cardiology, The Charité - University Medical School of Berlin, Campus Buch and Campus Virchow Clinics, Berlin, Germany

^* Author for correspondence (e-mail: salim{at}mdc-berlin.de)

Accepted 15 February 2006

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.

Key words: gp330, Cubilin, Disabled 2, Kidney, Endocytosis, PRKCiota, Mpp5

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