nephrin and Neural-Tube-Defects

Glomerular podocytes are highly polarized cells characterized by dynamic actin-based foot processes (FPs). Neighboring FPs form specialized junctions, slit diaphragms (SDs), which prevent passage of proteins into the ultrafiltrate. The SD protein complex is linked to cytoskeletal actin filaments and mutations in SD proteins lead to a dramatic change in cell morphology; proteinuria is accompanied by FP retraction and loss of SD structure. Thus, organization of the podocyte cytoskeleton is tightly linked to filtration barrier function. In a variety of cell systems, cytoskeleton arrangement is regulated by the planar cell polarity (PCP) pathway. PCP signals lead to the appearance of highly organized cellular structures that support directional cell movement and oriented cell division. Derangement of the PCP pathway causes neural tube defects and cystic kidney disease in mice. Here, we establish that the PCP pathway regulates the cytoskeleton of podocytes. We identify expression of core PCP proteins in mouse kidney sections and of PCP transcripts in murine and human cultured podocytes. The pathway is functional since Wnt5a causes redistribution of PCP proteins Dishevelled and Daam1. We also show that Wnt5a treatment changes podocyte morphology, alters nephrin distribution, increases the number of stress fibers, and increases cell motility. In reciprocal experiments, siRNA depletion of the core PCP gene Vangl2 reduced the number of cell projections and decreased stress fibers and cell motility. Finally, we demonstrate direct interactions between Vangl2 and the SD protein, MAGI-2. This suggests that the PCP pathway may be directly linked to organization of the SD as well as to regulation of podocyte cytoskeleton. Our observations indicate that PCP signaling may play an important role both in podocyte development and FP cytoskeleton dynamics.

Topics: Actins; Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Cell Line; Cell Movement; Cell Polarity; Cell Shape; Cytoskeletal Proteins; Cytoskeleton; Dishevelled Proteins; Guanylate Kinases; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Diseases, Cystic; Kidney Glomerulus; Membrane Proteins; Mice; Microfilament Proteins; Nerve Tissue Proteins; Neural Tube Defects; Phosphoproteins; Podocytes; Proteins; Proto-Oncogene Proteins; rho GTP-Binding Proteins; Wnt Proteins; Wnt-5a Protein