Klin Padiatr 2011; 223 - V01
DOI: 10.1055/s-0031-1273781

The polarity protein scribble interacts with Neph1 during glomerular development

M Schmidts 1, B Hartleben 2, B Mayer 2, L Schneider 2, N Wanner 2, E Widmeier 2, G Walz 2, T Huber 2
  • 1Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Freiburg, Freiburg i. Br.
  • 2Nehphrologie, Universitätsklinikum Freiburg, Freiburg

Objectives and Study: The glomerular filtration barrier is a unique structure characterized by a specialized three-dimensional framework of podocytes. Mutations in genes encoding for slitdiaphragm proteins Nephrin (NPHS1) and Podocin (NPHS2) cause a hereditary nephrotic syndrome in humans and genetic deletion of Neph1, a slit diaphragm protein closely related toNephrin, leads to congenital nephrotic syndrome in mice. An apico-basal polarity axis allows for podocyte orientation between the urinary space and the glomerular basement membrane. Our recent studies document that conserved polarity protein complexes such as the Par3, Par6 and aPKC (PAR) complex co-localize with the Nephrin complex and are essential regulators of podocyte morphology. Glomerular development, slit diaphragm targeting and apico-basolateral distribution of molecules seems to be tightly regulated by these polarity signaling pathways.

Methods: Immunoprecipitation,Immunofluorescence, shRNA knockdown, knock-out mouse.

Results: We identified the polarity molecule Scribble as novel Neph1- associated protein. The fourth PDZ domain of Scribble mediates the interaction with the conserved carboxy terminal residues in Neph1. Scribble co-localizes with Neph1 in podocyte foot processes during glomerular development. Strikingly, Scribble translocates together with apical junctionproteins like ZO–1 to the basolateral side of maturing podocytes. A scribble knockdwon via shRNA in cultured podocytes surprisingly did not affect podocyte survival or cell migratory abilities. To further investigate what role Scribble plays for glomerular development, maintenance and podocyte integrity a conditional scribble knock-out mouse is currently under investigation.

Conclusions: Our data provide an important link between cell recognition mediated through the Neph1-Nephrin complex and Scribble-dependant polarity signaling.

Neph1 - Scribble - glomerular development - nephrotic syndrome - podocyte