Wnt-4 activates the canonical β-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/β-catenin activity in kidney epithelial cells

Lyons, Jon P.; Mueller, Ulrich; Ji, Hong; Everett, C M; Fang, Xiang; Hsieh, Jen Chih; Barth, Angelai M.; McCrea, Pierre D.

doi:10.1016/j.yexcr.2004.04.036

Cited by 130 publications

(126 citation statements)

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“…The specific pathway used by each of the Wnts involved in the development of the metanephric kidney is unknown. In fact, examination of the expression of pathway components and target genes suggests that the canonical, PCP and calcium branches are all active during metanephric kidney development [7,[56][57][58][59]. The challenge now is identifying the ligands that mediate signaling through each branch and the cellular processes they regulate.…”

Section: The Role Of Wnt Signaling In Branching Morphogenesismentioning

confidence: 99%

“…This contradiction could be rectified if one assumed that Wnt9b acted in a canonical manner to stimulate Wnt4 expression, which subsequently induced tubulogenesis through the PCP pathway. However, studies using Madin-Darby canine kidney (MDCK) cells have shown that Wnt4 can activate a β-catenin/LEF/TCF luciferase reporter and Wnt4 can stabilize β-catenin in isolated MM, suggesting that it signals through the canonical branch [42,57]. Therefore, an alternative model is that the canonical Wnt signaling pathway, mediated by Wnt9b and/or Wnt4, is involved in the early stages of nephrogenesis, driving cell adhesion and/or cell proliferation (This hypothesis supposes that axin2 and Bat-Gal are not faithful reporters of canonical pathway activity in the MM.).…”

Section: Pathway Usage In Renal Vesicle Formationmentioning

confidence: 99%

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Molecular regulation of kidney development: is the answer blowing in the Wnt?

2007

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Development of the metanephric kidney is a complicated process regulated by reciprocal signals from the ureteric bud and the metanephric mesenchyme that regulate tubule formation and epithelial branching morphogenesis. Over the past several years, several studies have suggested that Wnt signaling is involved in multiple aspects of normal kidney development as well as injury response and cancer progression. We will review these data here.

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Section: The Role Of Wnt Signaling In Branching Morphogenesismentioning

confidence: 99%

Section: Pathway Usage In Renal Vesicle Formationmentioning

confidence: 99%

Molecular regulation of kidney development: is the answer blowing in the Wnt?

2007

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“…On the other hand, there is also evidence that WNT4 may have a set of effects mediated through the canonical ␤-catenin signaling pathway (13). This intracellular pathway responds to WNT activation of heterodimeric frizzled/LRP6 receptors at the surface of target cells (20).…”

Section: Potential Functions Of the Pax2/wnt4 Pathway Duringmentioning

confidence: 99%

“…In general, WNTs are thought to transmit signals to nearby cells bearing cognate receptors, thereby organizing cell alignment and tissue patterns during development (12). WNT4 was recently shown to be capable of activating the "canonical" ␤-catenin signaling pathway and therefore presumably regulates ␤-catenin-responsive gene targets, such as c-Myc, involved in cellular growth (13).…”

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confidence: 99%

PAX2 Activates WNT4 Expression during Mammalian Kidney Development

Torban

Dziarmaga

Iglesias

et al. 2006

Journal of Biological Chemistry

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The transcription factor PAX2 is expressed during normal kidney development and is thought to influence outgrowth and branching of the ureteric bud. Mice with homozygous null Pax2 mutations have developmental defects of the midbrain-hindbrain region, optic nerve, and ear and are anephric. During nephrogenesis, PAX2 is also expressed by mesenchymal cells as they cluster and reorganize to form proximal elements of each nephron, but the function of PAX2 in these cells is unknown. In this study we hypothesized that PAX2 activates expression of WNT4, a secreted glycoprotein known to be critical for successful nephrogenesis. PAX2 protein was identified in distal portions of the "S-shaped" body, and the protein persists in the emerging proximal tubules of murine fetal kidney. PAX2 activated WNT4 promoter activity 5-fold in co-transfection assays with JTC12 cells derived from the proximal tubule. Inspection of the 5-flanking sequence of the human WNT4 gene identified three novel PAX2 recognition motifs; each exhibited specific PAX2 protein binding in electromobility shift assays. Two motifs were contained within a completely duplicated 0.66-kb cassette. Transfection of JTC12 cells with a PAX2 expression vector was associated with a 7-fold increase in endogenous WNT4 mRNA. In contrast, Wnt4 mRNA was decreased by 60% in mesenchymal cell condensates of fetal kidney from mice with a heterozygous Pax2 mutation. We speculated that a key function of PAX2 is to activate WNT4 gene expression in metanephric mesenchymal cells as they differentiate to form elements of the renal tubules.PAX2 belongs to the "paired box" family of transcription factors. Like other family members, it is thought to orchestrate the patterns of gene expression in specific cells during organ development. Homozygous inactivation of the Pax2 gene in mice causes malformation of the midbrain-hindbrain region, the optic nerve, and complete absence of the kidneys (1, 2). Although these observations clearly implicate PAX2 in the development of renal and neural tissue, little is known about its precise gene targets or the specific developmental processes in which it plays a role.Studies thus far suggest that the developmental functions of PAX2 may be multiplex, activating distinct panels of genes in different cell lineages at different stages. During development of mammalian kidney, PAX2 first appears during the caudal descent of the nephric duct where it affects the fate of a cell (3). When the nephric duct arrives at about somite 26, a "ureteric bud" (UB) 2 emerges from its wall and grows toward the adjacent lateral mesenchyme. This event is again orchestrated by PAX2 through activation of glial cell line-derived neurotropic Factor (GDNF) in the uninduced mesenchyme and activation of the GDNF receptor (RET) in UB cells (4). Thus, homozygous Pax2 knockout mice lack normal ureteric bud outgrowth and are unable to induce metanephric kidneys (2).A third function of PAX2 in developing kidney involves suppression of programmed cell death in ureteric bud cells. During ...

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“…WNT4 and WNT9b signal through the canonical WNT signaling pathway. 31,32 WNT4, expressed by mesenchymal pretubular aggregates, is required for induction of metanephric mesenchyme-derived epithelial aggregates. 33 PAX2 activates Wnt4 expression, 34 suggesting that SHH may control Wnt4 indirectly through PAX2.…”

mentioning

confidence: 99%