Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.
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.
Anzenberger
Uwe
U
Max Delbrueck Center (MDC) for Molecular Medicine, Robert-Roessle Str. 10, 13125 Berlin, Germany.
Bit-Avragim
Nana
N
Rohr
Stefan
S
Rudolph
Franziska
F
Dehmel
Bastian
B
Willnow
Thomas E
TE
Abdelilah-Seyfried
Salim
S
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*
D033942:Adaptor Proteins, Vesicular Transport; D026561:Low Density Lipoprotein Receptor-Related Protein-2