Polycystin Signaling Is Required for Directed Endothelial Cell Migration and Lymphatic Development

• Pkd1−/− and Pkd2−/− embryos develop edema that is visible by E12.5
• Edema is associated with reduced lymphatic vessel density and vascular branching
• Pkd mutant endothelial cells have a defect in directed migration
• Knockdown of Pkd1and Pkd2 in ECs results in failure to establish front-rear polarity

SummaryAutosomal dominant polycystic kidney disease is a common form of inherited kidney disease that is caused by mutations in two genes, PKD1 (polycystin-1) and PKD2 (polycystin-2). Mice with germline deletion of either gene die in midgestation with a vascular phenotype that includes profound edema. Although an endothelial cell defect has been suspected, the basis of this phenotype remains poorly understood. Here, we demonstrate that edema in Pkd1- and Pkd2-null mice is likely to be caused by defects in lymphatic development. Pkd1 and Pkd2 mutant embryos exhibit reduced lymphatic vessel density and vascular branching along with aberrant migration of early lymphatic endothelial cell precursors. We used cell-based assays to confirm that PKD1- and PKD2-depleted endothelial cells have an intrinsic defect in directional migration that is associated with a failure to establish front-rear polarity. Our studies reveal a role for polycystin signaling in lymphatic development.

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