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Peptides from the PKD repeats of polycystin, the PKD1 gene product, modulate pattern formation in the developing
1Department of Medicine, Columbia University, New York, New York 10032, USA. jsv1@columbia.edu
Insights
Mutations in the PKD1 gene cause polycystic kidney disease. Peptides from polycystin-1 disrupt kidney development, suggesting its role in ureteric bud branching.
Area of Science:
- Nephrology
- Developmental Biology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is primarily caused by mutations in the PKD1 gene.
- The PKD1 gene encodes polycystin-1, a protein with a predicted receptor function and a large extracellular domain containing novel PKD repeats.
- Polycystin-1 interacts with beta-catenin and is expressed in developing ureteric buds, suggesting a role in branching morphogenesis.
Purpose of the Study:
- To investigate the function of polycystin-1 in kidney development.
- To determine if soluble fragments of polycystin-1 can inhibit its function.
- To explore the role of polycystin-1 in ureteric bud branching morphogenesis.
Main Methods:
- Cultured kidney rudiments were treated with peptides derived from polycystin-1's PKD repeats.
- Experimental and control peptides were used to assess effects on ureteric bud branching.
- The number of ureteric bud branches and nephrons was quantified.
Main Results:
- Peptides derived from PKD repeats induced asymmetric ureteric bud branching.
- Treatment with experimental peptides significantly reduced ureteric bud branches and nephron number.
- Significant morphogenetic effects were observed at concentrations as low as 0.1 mM.
Conclusions:
- Polycystin-1 plays a crucial role in ureteric bud branching morphogenesis.
- Soluble fragments of polycystin-1 can act as competitive inhibitors of its function.
- These findings provide insights into the molecular mechanisms underlying kidney development and ADPKD.
Abstract:
Mutations in the PKD1 gene cause the majority of cases of autosomal dominant polycystic kidney disease. The PKD1 gene codes for a protein of unknown function, polycystin-1, that is predicted to be a receptor. Its large extracellular domain contains 16 copies of novel motif, the PKD repeat, that is likely to be a ligand binding domain based on its similarity to immunoglobulin domains. These observations suggested that soluble fragments of the extracellular domain of polycystin-1 could be used as competitive inhibitors of polycystin function in a suitable model system. Polycystin-1 is highly expressed in the ureteric bud and other branching epithelia during development and interacts with beta-catenin, a molecule known to play a role in branching morphogenesis. These data suggested that polycystin-1 might play a role in branching morphogenesis. I show here that peptides derived from the PKD repeats of polycystin-1 caused an asymmetric pattern of ureteric bud branching in cultured kidney rudiments. Treatment of kidney rudiments with experimental but not control peptides reduced both the number of ureteric bud branches and the number of nephrons. Experimental peptides produced significant morphogenetic effects at concentrations < or = 0.1 mM. These data suggest that polycystin-1 plays a role in branching morphogenesis by the ureteric bud.