Apical Lumen Formation in Renal Epithelia

Schlüter, Marc A.; Margolis, Ben

doi:10.1681/asn.2008090949

Cited by 60 publications

(59 citation statements)

References 107 publications

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“…This is of particular interest with regard to the participation of TAZ in polycystic kidney disease because it has been hypothesized that tight junction and polarity proteins might also be involved in PKD (28). A well maintained apicobasal polarity is fundamental to renal tubule development and maturation because it coordinates the proper distribution of receptors, transporters, and channels (29,30). Cell polarity defects may result in aberrant renal epithelial organization and tubulogenesis and consequently induce cystogenesis in the epithelial tissues.…”

Section: Resultsmentioning

confidence: 99%

Polycystin-2 Activity Is Controlled by Transcriptional Coactivator with PDZ Binding Motif and PALS1-associated Tight Junction Protein

Duning

Rosenbusch

Schlüter

et al. 2010

Journal of Biological Chemistry

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Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic cause of kidney failure, characterized by the development of renal cysts. ADPKD is caused by mutations of the polycystin-1 (PC1) or polycystin-2 (PC2) genes. PC2 encodes a Ca 2؉ -permeable cation channel, and its dysfunction has been implicated in cyst development. The transcriptional coactivator with PDZ binding motif (TAZ) is required for the integrity of renal cilia. Its absence results in the development of renal cysts in a knock-out mouse model. TAZ directly interacts with PC2, and it has been suggested that another yet unidentified PDZ domain protein may be involved in the TAZ/PC2 interaction. Here we describe a novel interaction of TAZ with the multi-PDZ-containing PALS1-associated tight junction protein (PATJ). TAZ interacts with both the N-terminal PDZ domains 1-3 and the C-terminal PDZ domains 8 -10 of PATJ, suggesting two distinct TAZ binding domains. We also show that the C terminus of PC2 strongly interacts with PDZ domains 8 -10 and to a weaker extent with PDZ domains 1-3 of PATJ. Finally, we demonstrate that both TAZ and PATJ impair PC2 channel activity when co-expressed with PC2 in oocytes of Xenopus laevis. These results implicate TAZ and PATJ as novel regulatory elements of the PC2 channel and might thus be involved in ADPKD pathology.

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Section: Resultsmentioning

confidence: 99%

Polycystin-2 Activity Is Controlled by Transcriptional Coactivator with PDZ Binding Motif and PALS1-associated Tight Junction Protein

Duning

Rosenbusch

Schlüter

et al. 2010

Journal of Biological Chemistry

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“…Many of the general concepts that describe the cellular and molecular mechanisms underlying lumen formation have been derived from cell culture models or 2D images (Datta et al, 2011;Schlüter and Margolis, 2009). In this study, we provide a novel paradigm for de novo lumen formation and elongation in developing nephrons (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The cellular and molecular mechanisms that underlie the spatial and temporal formation of de novo lumen formation in developing nephrons are largely unknown. Indeed, much of our knowledge of renal epithelial lumen formation and morphogenesis is derived from cell culture models that may not accurately represent the process in vivo (Datta et al, 2011;Schlüter and Margolis, 2009). …”

Section: Introductionmentioning

confidence: 99%

De novo lumen formation and elongation in the developing nephron: a central role for afadin in apical polarity

et al. 2013

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SUMMARYA fundamental process in biology is the de novo formation and morphogenesis of polarized tubules. Although these processes are essential for the formation of multiple metazoan organ systems, little is known about the molecular mechanisms that regulate them. In this study, we have characterized several steps in tubule formation and morphogenesis using the mouse kidney as a model system. We report that kidney mesenchymal cells contain discrete Par3-expressing membrane microdomains that become restricted to an apical domain, coinciding with lumen formation. Once lumen formation has been initiated, elongation occurs by simultaneous extension and additional de novo lumen generation. We demonstrate that lumen formation and elongation require afadin, a nectin adaptor protein implicated in adherens junction formation. Mice that lack afadin in nephron precursors show evidence of Par3-expressing membrane microdomains, but fail to develop normal apical-basal polarity and generate a continuous lumen. Absence of afadin led to delayed and diminished integration of nectin complexes and failure to recruit R-cadherin. Furthermore, we demonstrate that afadin is required for Par complex formation. Together, these results suggest that afadin acts upstream of the Par complex to regulate the integration and/or coalescence of membrane microdomains, thereby establishing apical-basal polarity and lumen formation/elongation during kidney tubulogenesis.

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“…Our work is focused on the apical polarity protein called Crumbs3. [30][31][32] Crumbs was first described…”

Section: The Ciliary Pore and The Role Of The Ran/importin Systemmentioning

confidence: 99%

The Ran importin system in cilia trafficking

Fan

Margolis

2011

Organogenesis

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C ilia are microtubule-based organelles that arise from the centrosome and project from the surface of many cells. Defects in cilia-localized proteins are felt to lead to polycystic kidney disease as well as ciliopathies with multiple organ involvement. Movement of proteins along mammalian cilia is a specialized process that is highly related to the intraflagellar movement of proteins in lower organisms. Entry of proteins into the cilia appears to be a tightly regulated process. Several cilia-targeting sequences have been identified that appear to mediate the movement of proteins into cilia, although the molecular basis through which these sequences operate is still being elucidated. Entry of proteins into cilia appears to be regulated at the base of the cilia at a region known as the transition zone. It has been proposed that a ciliary pore exists in this zone that controls entry of proteins into the cilia, similar to the nuclear pore that controls entry of proteins into the nucleus. Our group at the University of Michigan has found that proteins important in nuclear import appear to function similarly in cilia entry. In particular, we have identified roles for the small GTPase, Ran and its binding partners, the importins, in regulating cilia entry of specific proteins.

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Apical Lumen Formation in Renal Epithelia

Cited by 60 publications

References 107 publications

Polycystin-2 Activity Is Controlled by Transcriptional Coactivator with PDZ Binding Motif and PALS1-associated Tight Junction Protein

Polycystin-2 Activity Is Controlled by Transcriptional Coactivator with PDZ Binding Motif and PALS1-associated Tight Junction Protein

De novo lumen formation and elongation in the developing nephron: a central role for afadin in apical polarity

The Ran importin system in cilia trafficking

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