Unexpected Roles of the Na-K-ATPase and Other Ion Transporters in Cell Junctions and Tubulogenesis

Krupinski, Thomas; Beitel, Greg J.

doi:10.1152/physiol.00008.2009

Cited by 34 publications

(23 citation statements)

References 85 publications

(110 reference statements)

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“…Similarly, claudins do not appear to be required for epithelial polarity in mammalian epithelial cells, since Eph4 cells can establish normal polarity even when lacking claudin complexes and tight junction strands due to elimination of ZO-1 and ZO-2 (Umeda et al 2006). The absence of a role for claudins in polarity in any characterized species is consistent with the proposal that barrier junctions arose after polarity during the evolution of metazoans (Krupinski and Beitel 2009). …”

Section: Resultssupporting

confidence: 82%

The Drosophila Claudin Kune-kune Is Required for Septate Junction Organization and Tracheal Tube Size Control

2010

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The vertebrate tight junction is a critical claudin-based cell-cell junction that functions to prevent free paracellular diffusion between epithelial cells. In Drosophila, this barrier is provided by the septate junction, which, despite being ultrastructurally distinct from the vertebrate tight junction, also contains the claudin-family proteins Megatrachea and Sinuous. Here we identify a third Drosophila claudin, Kunekune, that localizes to septate junctions and is required for junction organization and paracellular barrier function, but not for apical-basal polarity. In the tracheal system, septate junctions have a barrierindependent function that promotes lumenal secretion of Vermiform and Serpentine, extracellular matrix modifier proteins that are required to restrict tube length. As with Sinuous and Megatrachea, loss of Kune-kune prevents this secretion and results in overly elongated tubes. Embryos lacking all three characterized claudins have tracheal phenotypes similar to any single mutant, indicating that these claudins act in the same pathway controlling tracheal tube length. However, we find that there are distinct requirements for these claudins in epithelial septate junction formation. Megatrachea is predominantly required for correct localization of septate junction components, while Sinuous is predominantly required for maintaining normal levels of septate junction proteins. Kune-kune is required for both localization and levels. Double-and triple-mutant combinations of Sinuous and Megatrachea with Kunekune resemble the Kune-kune single mutant, suggesting that Kune-kune has a more central role in septate junction formation than either Sinuous or Megatrachea.

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Section: Resultssupporting

confidence: 82%

The Drosophila Claudin Kune-kune Is Required for Septate Junction Organization and Tracheal Tube Size Control

2010

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“…A number of polarity and cell junction complexes prevent the free flow of molecules between cells and help to establish ionic gradients. For example, the Na + /K + ATPase protein is localized to basolateral sides of nephron epithelia and has roles in ion transport and tight junction assembly (Rajasekaran, et al, 2001; Krupinski, et al, 2009). The mislocalization of Na + /K + ATPase has been observed in human renal disease and in zebrafish kidney mutants that develop edema (Wilson, 2011; Drummond, et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Zebrafish pronephros tubulogenesis and epithelial identity maintenance are reliant on the polarity proteins Prkc iota and zeta

Gerlach

Wingert

2014

Developmental Biology

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The zebrafish pronephros provides an excellent in vivo system to study the mechanisms of vertebrate nephron development. When and how renal progenitors in the zebrafish embryo undergo tubulogenesis to form nephrons is poorly understood, but is known to involve a mesenchymal to epithelial transition (MET) and the acquisition of polarity. Here, we determined the precise timing of these events in pronephros tubulogenesis. As the ternary polarity complex is an essential regulator of epithelial cell polarity across tissues, we performed gene knockdown studies to assess the roles of the related factors atypical protein kinase C iota and zeta (prkcι, prkcζ). We found that prkcι and prkcζ serve partially redundant functions to establish pronephros tubule epithelium polarity. Further, the loss of prkcι or the combined knockdown of prkcι/ζ disrupted proximal tubule morphogenesis and podocyte migration due to cardiac defects that prevented normal fluid flow to the kidney. Surprisingly, tubule cells in prkcι/ζ morphants displayed ectopic expression of the transcription factor pax2a and the podocyte-associated genes wt1a, wt1b, and podxl, suggesting that prkcι/ζ are needed to maintain renal epithelial identity. Knockdown of genes essential for cardiac contractility and vascular flow to the kidney, such as tnnt2a, or elimination of pronephros fluid output through knockdown of the intraflagellar transport gene ift88, was not associated with ectopic pronephros gene expression, thus suggesting a unique role for prkcι/ζ in maintaining tubule epithelial identity separate from the consequence of disruptions to renal fluid flow. Interestingly, knockdown of pax2a, but not wt1a, was sufficient to rescue ectopic tubule gene expression in prkcι/ζ morphants. These data suggest a model in which the redundant activities of prkcι and prkcζ are essential to establish tubule epithelial polarity and also serve to maintain proper epithelial cell type identity in the tubule by inhibiting pax2a expression. These studies provide a valuable foundation for further analysis of MET during nephrogenesis, and have implications for understanding the pathways that affect nephron epithelial cells during kidney disease and regeneration.

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“…glucose and neurotransmitters. In addition, Na,K-ATPase may have pump-independent functions, and in particular is known to contribute to the formation of cell-cell contacts (Genova and Fehon 2003;Vagin et al 2006;Paul et al 2007;Krupinski and Beitel 2009), maintenance of epithelial polarity (Laprise et al 2009), and signal transduction (Kometiani et al 1998;Aydemir-Koksoy et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Developmental changes in β-subunit composition of Na,K-ATPase in the Drosophila eye

Baumann

Salvaterra

2010

Cell Tissue Res

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The Drosophila genome contains at least three loci for the Na,K-ATPase beta-subunit; however, only the protein products of nrv1 and nrv2 have been characterized hitherto. Here, we provide evidence that nrv3 also encodes for a functional Na,K-ATPase beta-subunit, as its protein product co-precipitates with the Na,K-ATPase alpha-subunit. Nrv3 expression in adult flies is restricted to the nervous system in which Nrv3 is enriched in selective types of sensory cells. Because Nrv3 expression is especially prominent in the compound eye, we have analyzed the subcellular and developmental distribution of Nrv3 within the visual cells and related this distribution to those of the alpha-subunit and of the beta-subunits Nrv1 and Nrv2. Prospective visual cells express Nrv2 in the third larval instar stage and during the first half of pupal development. During the last third of pupal life, Nrv3 gradually replaces Nrv2 as the Na,K-ATPase beta-subunit in the photoreceptor cells. Adult photoreceptors express Nrv3 as their major beta-subunit; the visual cells R1-R6 co-express Nrv2 at a low level, whereas R7 and R8 co-express Nrv1. Notably, beta-subunits do not co-distribute exactly with the alpha-subunit at some developmental stages, supporting the concept that the alpha-subunit and beta-subunit can exist in the plasma membrane without being engaged in alpha/beta heterodimers. The non-visual cells within the compound eye express almost exclusively Nrv2, which segregates together with the alpha-subunit to septate junctions throughout development.

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Unexpected Roles of the Na-K-ATPase and Other Ion Transporters in Cell Junctions and Tubulogenesis

Cited by 34 publications

References 85 publications

The Drosophila Claudin Kune-kune Is Required for Septate Junction Organization and Tracheal Tube Size Control

The Drosophila Claudin Kune-kune Is Required for Septate Junction Organization and Tracheal Tube Size Control

Zebrafish pronephros tubulogenesis and epithelial identity maintenance are reliant on the polarity proteins Prkc iota and zeta

Developmental changes in β-subunit composition of Na,K-ATPase in the Drosophila eye

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