β-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors

Schmidt‐Ott, Kai M.; Masckauchán, T. Néstor H.; Chen, Xia; Hirsh, Benjamin; Sarkar, Abby; Yang, Jun; Paragas, Neal; Wallace, Valerie A.; Dufort, Daniel; Pavlidis, Paul; Jagla, Bernd; Kitajewski, Jan; Barasch, Jonathan

doi:10.1242/dev.006544

Cited by 90 publications

(100 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, WTX may function in concert with WT1, possibly as a cofactor during kidney development (Rivera et al, 2009). The Wnt pathway is essential for normal kidney development and enforced expression of activated b-catenin leads to hyperproliferation of the putative metanephric mesenchyme leading to overgrowths that resemble the blastemal elements of Wilms tumor (Park et al, 2007;Schmidt-Ott et al, 2007). WT1 and WTX may both act to limit the extent of Wnt signaling as the metanephric mesenchyme condenses into mature epithelial structures.…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

et al. 2010

View full text Add to dashboard Cite

The WTX, Wilms tumor-associated tumor-suppressor gene, is present on the X chromosome and a single WTX mutation may be sufficient to promote carcinogenesis. Unlike the WT1 tumor suppressor, a transcription factor, WTX lacks conserved functional protein domains. To study the function of WTX, we constructed inducible cell lines expressing WTX and tumor-associated WTX mutants. Induction of WTX inhibited cell growth and caused G 1 /G 0 arrest. In contrast, a short, tumorassociated truncation mutant of WTX358 only slightly inhibited cell growth without a significant cell-cycle arrest, although expression of a longer truncation mutant WTX565 led to the growth inhibition and cell-cycle arrest to a similar extent as wild-type WTX. Like WT1, WTX slowed growth and caused cell-cycle arrest through p21 induction. Gene expression profiling showed that these two tumorsuppressors regulated genes in similar pathways, including those implicated in control of the cellular growth, cell cycle, cell death, cancer and cardiovascular system development. When gene expression changes mediated by wild-type WTX were compared with those affected by mutant forms, WTX565 showed a 55% overlap (228 genes) in differentially regulated genes, whereas WTX358 regulated only two genes affected by wild-type WTX, implying that amino-acid residues 358-561 are critical for WTX function.

show abstract

Section: Discussionmentioning

confidence: 99%

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

et al. 2010

View full text Add to dashboard Cite

show abstract

“…LacZ staining was carried out as described previously (Zhang et al, 2009). Whole-mount or section in situ hybridization on embryos or kidneys was carried out as described previously (Hammes et al, 2001;Schmidt-Ott et al, 2007). Riboprobes for E-cadherin and Cldn4 were produced from PCR fragments (see Table S1 in the supplementary material).…”

Section: Immunofluorescence Staining Lacz Staining and In Situ Hybrimentioning

confidence: 99%

“…Conversely, Ecadherin transcription is re-induced in mesenchymal cells that undergo epithelial conversion during kidney development. Remarkably, in this context, the induction of E-cadherin is temporally coordinated with the expression of multiple additional components of the apical junctional complex, suggesting that a common molecular mechanism orchestrates the induction of apical junctional complex components during epithelial differentiation (Schedl, 2007;Schmidt-Ott et al, 2007).…”

Section: Introductionmentioning

confidence: 96%

The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex

et al. 2010

Self Cite

View full text Add to dashboard Cite

Differentiation of epithelial cells and morphogenesis of epithelial tubes or layers is closely linked with the establishment and remodeling of the apical junctional complex, which includes adherens junctions and tight junctions. Little is known about the transcriptional control of apical junctional complex components. Here, we show that the transcription factor grainyhead-like 2 (Grhl2), an epithelium-specific mammalian homolog of Drosophila Grainyhead, is essential for adequate expression of the adherens junction gene E-cadherin and the tight junction gene claudin 4 (Cldn4) in several types of epithelia, including gut endoderm, surface ectoderm and otic epithelium. We have generated Grhl2 mutant mice to demonstrate defective molecular composition of the apical junctional complex in these compartments that coincides with the occurrence of anterior and posterior neural tube defects. Mechanistically, we show that Grhl2 specifically associates with cis-regulatory elements localized at the Cldn4 core promoter and within intron 2 of the E-cadherin gene. Cldn4 promoter activity in epithelial cells is crucially dependent on the availability of Grhl2 and on the integrity of the Grhl2-associated cis-regulatory element. At the E-cadherin locus, the intronic Grhl2-associated cis-regulatory region contacts the promoter via chromatin looping, while loss of Grhl2 leads to a specific decrease of activating histone marks at the E-cadherin promoter. Together, our data provide evidence that Grhl2 acts as a target gene-associated transcriptional activator of apical junctional complex components and, thereby, crucially participates in epithelial differentiation.

show abstract

“…25 Elegant studies have shown that WNT/b-catenin signaling is a necessary and sufficient trigger of the early stages of nephron differentiation. 26,27 We linked the human WNT4 variant to defective WNT signaling by two independent model systems. In the first model, utilizing HEK293, WNT4 by itself does not trigger WNT/b-catenin signaling but rather inhibits a Wnt3A-induced signal, whereas the WNT4 variant induces significantly exaggerated inhibition.…”

Section: T G G a A G T C A T G G A C T C G Gmentioning

confidence: 99%

Renal Hypodysplasia Associates with a Wnt4 Variant that Causes Aberrant Canonical Wnt Signaling

Vivante

Mark‐Danieli

Davidovits

et al. 2013

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF, WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonical WNT stimuli, dependent on cell type. In HEK293 cells, WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/b-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.

show abstract

β-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors

Cited by 90 publications

References 50 publications

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex

Renal Hypodysplasia Associates with a Wnt4 Variant that Causes Aberrant Canonical Wnt Signaling

Contact Info

Product

Resources

About