β-Catenin Overexpression in the Metanephric Mesenchyme Leads to Renal Dysplasia Genesis via Cell-Autonomous and Non–Cell-Autonomous Mechanisms

Sarin, Sanjay; Boivin, Félix; Li, Aihua; Lim, Janice; Svajger, Bruno; Rosenblum, Norman D.; Bridgewater, Darren

doi:10.1016/j.ajpath.2014.01.018

Cited by 24 publications

(49 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the histopathological hallmarks of human renal dysplasia is the focal expansion of stromal cells (Figures A and B). We analysed three different human renal dysplastic tissues and observed increased nuclear β‐catenin within the expanded stromal cells (Figures C and D), which was also observed in our previous reports . Next, we sought to determine the functional significance of β‐catenin overexpression in the renal stroma.…”

Section: Resultssupporting

confidence: 66%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 66%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Reduced arborization of the UB ultimately translates into fewer nephrons since each UB tip provides inductive cues for conversion of the adjacent cap mesenchyme into a nephron [113]. The renal phenotype of either Wnt5a or Wnt11 mutant mice is reminiscent of the phenotypes observed in mice with deregulation of canonical Wnt/ -catenin pathway: for example, overexpression of -catenin in mesonephric mesenchyme results in ND patterning defects, excessive expression of Ret, and extranumerary kidneys [21]; loss ofcatenin in UB reduces UB branching culminating in severe renal hypoplasia [22]. One possibility is that, during kidney development, Wnt5 and Wnt11 participate in both Wnt/ -catenin and PCP signaling.…”

Section: Planar Cell Polarity Pathway and Kidneymentioning

confidence: 84%

“…A set of transcription factors (e.g., Six2 and Osr1) define cap mesenchyme-derived progenitor cells which give rise to the majority of nephron segments [18,19]. Action of the Wnt/ -catenin pathway is crucial for the survival and self-renewal of nephron progenitor cells, MET induction, and UB branching [20][21][22]. The transcription factor PAX2 is a key regulator of early kidney development.…”

Section: Mammalian Kidney Developmentmentioning

confidence: 99%

Planar Cell Polarity Pathway in Kidney Development and Function

Rocque

Torban

2015

Advances in Nephrology

View full text Add to dashboard Cite

The evolutionarily conserved planar cell polarity (PCP) signaling pathway controls tissue polarity within the plane orthogonal to the apical-basal axis. PCP was originally discovered in Drosophila melanogaster where it is required for the establishment of a uniform pattern of cell structures and appendages. In vertebrates, including mammals, the PCP pathway has been adapted to control various morphogenetic processes that are critical for tissue and organ development. These include convergent extension (crucial for neural tube closure and cochlear duct development) and oriented cell division (needed for tubular elongation), ciliary tilting that enables directional fluid flow, and other processes. Recently, strong evidence has emerged to implicate the PCP pathway in vertebrate kidney development. In this review, we will describe the experimental data revealing the role of PCP signaling in nephrogenesis and kidney disease.

show abstract

“…35 We also detected the diminished expression of GDNF in the renal primordia of Lrp6 mutant embryos. A recent study revealed that b-catenin directly regulates GDNF expression in renal mesenchyme, while b-catenin may also reciprocally interact with Ret in renal epithelia, 36 which supports a possible role of Ret in mediating Wnt/b-catenin signaling during nephrogenesis. The residual expression of Ret in the renal primordia of Lrp6-null embryos indicates that Ret may also be regulated by other factors, either Wnt-independent factors or the Wnt coreceptor Lrp5; the latter plays a functionally redundant role with Lrp6 during embryonic development.…”

Section: Ret As a Downstream Effecter Of Lrp6-mediated Wnt/b-catenin mentioning

confidence: 99%

LDL Receptor–Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia

Wang

Stokes

Duan

et al. 2016

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Hypoplastic and/or cystic kidneys have been found in both LDL receptor-related protein 6 (Lrp6)-and b-catenin-mutant mouse embryos, and these proteins are key molecules for Wnt signaling. However, the underlying mechanisms of Lrp6/b-catenin signaling in renal development and cystic formation remain poorly understood. In this study, we found evidence that diminished cell proliferation and increased apoptosis occur before cystic dysplasia in the renal primordia of Lrp6-deficient mouse embryos. The expression of Ret protooncogene (Ret), a critical receptor for the growth factor glial cell line-derived neurotrophic factor (GDNF), which is required for early nephrogenesis, was dramatically diminished in the mutant renal primordia. The activities of other representative nephrogenic genes, including Lim1, Pax2, Pax8, GDNF, and Wnt11, were subsequently diminished in the mutant renal primordia. Molecular biology experiments demonstrated that Ret is a novel transcriptional target of Wnt/b-catenin signaling. Wnt agonist lithium promoted Ret expression in vitro and in vivo. Furthermore, Lrp6-knockdown or lithium treatment in vitro led to downregulation or upregulation, respectively, of the phosphorylated mitogen-activated protein kinases 1 and 3, which act downstream of GDNF/ Ret signaling. Mice with single and double mutations of Lrp6 and Ret were perinatal lethal and demonstrated gene dosage-dependent effects on the severity of renal hypoplasia during embryogenesis. Taken together, these results suggest that Lrp6-mediated Wnt/b-catenin signaling modulates or interacts with a signaling network consisting of Ret cascades and related nephrogenic factors for renal development, and the disruption of these genes or signaling activities may cause a spectrum of hypoplastic and cystic kidney disorders.

show abstract

β-Catenin Overexpression in the Metanephric Mesenchyme Leads to Renal Dysplasia Genesis via Cell-Autonomous and Non–Cell-Autonomous Mechanisms

Cited by 24 publications

References 45 publications

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

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

Planar Cell Polarity Pathway in Kidney Development and Function

LDL Receptor–Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia

Contact Info

Product

Resources

About