Hartleben, B and Widmeier, E and Wanner, N and Schmidts, M and Kim, ST and Schneider, L and Mayer, B and Kerjaschki, D and Miner, JH and Walz, G and Huber, TB (2012) Role of the polarity protein Scribble for podocyte differentiation and maintenance. PLoS One , 7 (5) , Article e36705 . 10.1371/journal.pone.0036705.
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The kidney filter represents a unique assembly of podocyte epithelial cells that tightly enwrap the glomerular capillaries with their complex foot process network. While deficiency of the polarity proteins Crumbs and aPKC result in impaired podocyte foot process architecture, the function of basolateral polarity proteins for podocyte differentiation and maintenance remained unclear. Here we report, that Scribble is expressed in developing podocytes, where it translocates from the lateral aspects of immature podocytes to the basal cell membrane and foot processes of mature podocytes. Immunogold electron microscopy reveals membrane associated localisation of Scribble predominantly at the basolateral site of foot processes. To further study the role of Scribble for podocyte differentiation Scribble(flox/flox) mice were generated by introducing loxP-sites into the Scribble introns 1 and 8 and these mice were crossed to NPHS2.Cre mice and Cre deleter mice. Podocyte-specific Scribble knockout mice develop normally and display no histological, ultrastructural or clinical abnormalities up to 12 months of age. In addition, no increased susceptibility to glomerular stress could be detected in these mice. In contrast, constitutive Scribble knockout animals die during embryonic development indicating the fundamental importance of Scribble for embryogenesis. Like in podocyte-specific Scribble knockout mice, the development of podocyte foot processes and the slit diaphragm was unaffected in kidney cultures from constitutive Scribble knockout animals. In summary these results indicate that basolateral polarity signaling via Scribble is dispensable for podocyte function, highlighting the unique feature of podocyte development with its significant apical membrane expansions being dominated by apical polarity complexes rather than by basolateral polarity signaling.
|Title:||Role of the polarity protein Scribble for podocyte differentiation and maintenance.|
|Open access status:||An open access publication. A version is also available from UCL Discovery.|
|Additional information:||PMCID: PMC3346764 © 2012 Hartleben et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This study was supported by Else Kröner-Fresenius-Stiftung (T.B.H.), Deutsche Forschungsgemeinschaft SFB 592 (T.B.H.), the Excellence Initiative of the German Federal and State Governments EXC 294 (T.B.H.), Deutsche Nierenstiftung (B.H.), Peter-Stiftung für die Nierenwissenschaft (M.S.), and National Institutes of Health R01DK081156 and P30DK079333 (J.H.M. and S.T.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.|
|Keywords:||Animals, Carrier Proteins, Cell Differentiation, Cell Membrane, Cells, Cultured, Embryonic Development, Gene Expression Regulation, Developmental, Intracellular Signaling Peptides and Proteins, Kidney Glomerulus, Mice, Mice, Knockout, Podocytes, Rats, Rats, Wistar, Sialoglycoproteins, Signal Transduction|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Genes, Development and Disease > ICH - Molecular Medicine Unit|
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