Stromally Expressed β-Catenin Modulates Wnt9b Signaling in the Ureteric Epithelium

Boivin, Félix; Sarin, Sanjay; Lim, Janice; Javidan, Ashkan; Svajger, Bruno; Khalili, Hadiseh; Bridgewater, Darren

doi:10.1371/journal.pone.0120347

Cited by 31 publications

(65 citation statements)

References 28 publications

(44 reference statements)

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“…The altered stromal cell differentiation would disrupt the renal stroma's ability to properly communicate with the neighbouring ureteric epithelium and MM. We have previously demonstrated that stromal β‐catenin modulates Wnt9b gene expression in the neighbouring ureteric epithelium . We believe that Wnt9b in the ureteric epithelium is modulated by factors in the renal stroma that are regulated by β‐catenin.…”

Section: Discussionmentioning

confidence: 91%

“…We confirmed a 63% reduction of Pod1 expression in β‐cat GOF‐S mutants at E14.5 by RT‐qPCR (1.00 versus 0.37, p < 0.0001) (Figure F). Furthermore, using Pbx1 and Meis1/2, markers of all renal stromal cells , the majority of the expanded population of stromal cells in β‐cat GOF‐S kidneys did not express Pbx1 (Figures G and H) or Meis1/2 (Figures J and K). These results were confirmed by RT‐qPCR, which showed a 54% reduction in Pbx1 (WT 1.1 versus β‐cat GOF‐S 0.52, p = 0.044) (Figure I) and a 36% reduction in Meis1/2 (WT 1.01 versus β‐cat GOF‐S 0.654, p = 0.02) at E14.5 (Figure L).…”

Section: Resultsmentioning

confidence: 99%

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Stromal β-catenin overexpression contributes to the pathogenesis of renal dysplasia

et al. 2016

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Renal dysplasia, the leading cause of renal failure in children, is characterized by disrupted branching of the collecting ducts and primitive tubules, with an expansion of the stroma, yet a role for the renal stroma in the genesis of renal dysplasia is not known. Here, we demonstrate that expression of β-catenin, a key transcriptional co-activator in renal development, is markedly increased in the expanded stroma in human dysplastic tissue. To understand its contribution to the genesis of renal dysplasia, we generated a mouse model that overexpresses β-catenin specifically in stromal progenitors, termed β-cat(GOF-S) . Histopathological analysis of β-cat(GOF) (-S) mice revealed a marked expansion of fibroblast cells surrounding primitive ducts and tubules, similar to defects observed in human dysplastic kidneys. Characterization of the renal stroma in β-cat(GOF) (-S) mice revealed altered stromal cell differentiation in the expanded renal stroma demonstrating that this is not renal stroma but instead a population of stroma-like cells. These cells overexpress ectopic Wnt4 and Bmp4, factors necessary for endothelial cell migration and blood vessel formation. Characterization of the renal vasculature demonstrated disrupted endothelial cell migration, organization, and vascular morphogenesis in β-cat(GOF) (-S) mice. Analysis of human dysplastic tissue demonstrated a remarkably similar phenotype to that observed in our mouse model, including altered stromal cell differentiation, ectopic Wnt4 expression in the stroma-like cells, and disrupted endothelial cell migration and vessel formation. Our findings demonstrate that the overexpression of β-catenin in stromal cells is sufficient to cause renal dysplasia. Further, the pathogenesis of renal dysplasia is one of disrupted stromal differentiation and vascular morphogenesis. Taken together, this study demonstrates for the first time the contribution of stromal β-catenin overexpression to the genesis of renal dysplasia. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Stromal β-catenin overexpression contributes to the pathogenesis of renal dysplasia

et al. 2016

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“…Reduction in proximal tubule AGT protein levels in Foxd1 −/− kidneys may also be due to disruption of Foxd1-dependent signals that mediate the communication between the stromal and nephrogenic compartments. One potential signal may be stromally expressed β -catenin, reported to regulate the induction of nephrogenic progenitors (22). In support of this possibility, bioinformatic analyses reveal the presence of the consensus T-cell factor-binding sites in the regulatory regions of the AGT gene (23).…”

Section: Discussionmentioning

confidence: 99%

Foxd1 is an upstream regulator of the renin–angiotensin system during metanephric kidney development

2017

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BACKGROUND We tested the hypothesis that Foxd1, a transcription factor essential for normal kidney development, is an upstream regulator of the renin–angiotensin system (RAS) during ureteric bud (UB)-branching morphogenesis. METHODS UB branching, RAS gene, and protein expression were studied in embryonic mouse kidneys. RAS mRNA expression was studied in mesenchymal MK4 cells. RESULTS The number of UB tips was reduced in Foxd1−/− compared with that in Foxd1+/+ metanephroi on embryonic day E12.5 (14 ± 2.1 vs. 28 ± 1.3, P<0.05). Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) demonstrated that renin, angiotensin I-converting enzyme (ACE), and angiotensin (Ang) II receptor type 1 (AT1R) mRNA levels were decreased in Foxd1−/− compared with those in Foxd1+/+ E14.5 metanephroi. Western blot analysis and immunohistochemistry showed decreased expression of AGT and renin proteins in Foxd1−/− metanephroi compared with that in Foxd1+/+ metanephroi. Foxd1 overexpression in mesenchymal MK4 cells in vitro increased renin, AGT, ACE, and AT1R mRNA levels. Exogenous Ang II stimulated UB branching equally in whole intact E12.5 Foxd1−/− and Foxd1+/+ metanephroi grown ex vivo (+364 ± 21% vs. +336 ± 18%, P = 0.42). CONCLUSION We conclude that Foxd1 is an upstream positive regulator of RAS during early metanephric development and propose that the cross-talk between Foxd1 and RAS is essential in UB-branching morphogenesis.

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“…53 After deletion of β-catenin specifically in the kidney stroma, the fibroblasts in kidney capsule, cortex, and medulla, the expression of Wnt9b was markedly reduced in adjacent ureteric epithelial cells, suggesting the role of Wnt9b as effector downstream of β-catenin during induction of nephron progenitors. 54 It is interesting to note that Wnt9b participates in the planar cell polarity of epithelium and contributes to the size of tubular diameters. The mice with attenuation of Wnt9b exhibit randomly oriented cell divisions and significantly increase tubular diameter, which act through the noncanonical Rho/JNK pathway during kidney morphogenesis.…”

Section: Wnt Signaling and Kidney Developmentmentioning

confidence: 99%

Wnt Signaling in Kidney Development and Disease

Wang

Zhou

Liu

2018

Progress in Molecular Biology and Translational Science

110

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Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients.

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Stromally Expressed β-Catenin Modulates Wnt9b Signaling in the Ureteric Epithelium

Cited by 31 publications

References 28 publications

Stromal β-catenin overexpression contributes to the pathogenesis of renal dysplasia

Stromal β-catenin overexpression contributes to the pathogenesis of renal dysplasia

Foxd1 is an upstream regulator of the renin–angiotensin system during metanephric kidney development

Wnt Signaling in Kidney Development and Disease

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