Abstract
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 Scribbleflox/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.
Highlights
The glomerular filtration barrier is a unique structure characterized by a precise three dimensional framework of podocytes that elaborate long, regularly spaced, interdigitating foot processes, enveloping the glomerular capillaries
In epithelial cells apicobasal cell polarity is established by the asymmetric distribution of three core polarity complexes, the apical Crumbs complex, consisting of Crumbs, PALS1 and PATJ, the apical Par complex localizing at the tight junctions and the basolateral Scribble complex, comprising the proteins Scribble, Dlg and Lgl [3]
Translocation of apical and basolateral polarity proteins during podocyte differentiation Previously, we identified that the aPKC complex translocates from the apical to basal membranes during podocyte differentiation, preceding the development of primary and foot processes [5]
Summary
The glomerular filtration barrier is a unique structure characterized by a precise three dimensional framework of podocytes that elaborate long, regularly spaced, interdigitating foot processes, enveloping the glomerular capillaries. Neighbouring podocytes are connected by the slit diaphragm, a specialized cell junction and the only cell-cell contact of mature podocytes, that bridges the filtration slit between podocyte foot processes [1]. During podocyte differentiation the Par complex and the cell-cell contacts of immature podocytes migrate from apical towards basal aspects of the podocyte cell membrane, where primary processes and foot processes subsequently develop. In epithelial cells apicobasal cell polarity is established by the asymmetric distribution of three core polarity complexes, the apical Crumbs complex, consisting of Crumbs, PALS1 and PATJ, the apical Par complex localizing at the tight junctions and the basolateral Scribble complex, comprising the proteins Scribble, Dlg and Lgl [3]. In Zebrafish, morpholino knockdown of the apical polarity protein Crumbs2b causes disorganization of podocyte foot process architecture and loss of slit diaphragms [4]. The relevance of the basolateral Scribble complex for podocyte function is yet completely unclear
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