A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells

AbstractThe canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR9902 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs is independent of direct engagement of TCF/LEF/ β-catenin transcriptional complexes at low-CHIR dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter-enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin’s direct transcriptional role is restricted to the induction of NPCs where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.

Download Full-text

A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells

eLife ◽

10.7554/elife.64444 ◽

2021 ◽

Vol 10 ◽

Author(s):

Qiuyu Guo ◽

Albert D Kim ◽

Bin Li ◽

Andrew Ransick ◽

Helena Bugacov ◽

...

Keyword(s):

Progenitor Cells ◽

Wnt Pathway ◽

Target Genes ◽

De Novo ◽

Feedback Regulation ◽

Canonical Wnt Pathway ◽

Dependent Cell ◽

Nephron Progenitor ◽

Canonical Wnt ◽

Gsk3 Inhibitor

The canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR9902 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs is independent of direct engagement of TCF/LEF/β-catenin transcriptional complexes at low CHIR-dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter-enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin's direct transcriptional role is restricted to the induction of NPCs where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.

Download Full-text

Hepatic Progenitor Cells Contribute to the Progression of 2-Acetylaminofluorene/Carbon Tetrachloride-Induced Cirrhosis via the Non-Canonical Wnt Pathway

PLoS ONE ◽

10.1371/journal.pone.0130310 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0130310 ◽

Cited By ~ 8

Author(s):

Jiamei Chen ◽

Xiao Zhang ◽

Ying Xu ◽

Xuewei Li ◽

Shuang Ren ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Progenitor Cells ◽

Wnt Pathway ◽

Hepatic Progenitor Cells ◽

Canonical Wnt Pathway ◽

Canonical Wnt

Download Full-text

Canonical Wnt-Pathway and Cytoskeleton in Human Neural Progenitor Cells

10.1240/sav_gbm_2007_h_001922 ◽

2007 ◽

Vol 2007 (Fall) ◽

Author(s):

Benjamin M. Bader ◽

Dieter G. Weiss

Keyword(s):

Progenitor Cells ◽

Wnt Pathway ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Canonical Wnt Pathway ◽

Human Neural Progenitor Cells ◽

Canonical Wnt

Download Full-text

Impact of the Canonical Wnt Pathway Activation on the Pathogenesis and Prognosis of Adamantinomatous Craniopharyngiomas

Hormone and Metabolic Research ◽

10.1055/a-0593-5956 ◽

2018 ◽

Vol 50 (07) ◽

pp. 575-581 ◽

Cited By ~ 4

Author(s):

Carlos Jucá ◽

Leandro Colli ◽

Clarissa Martins ◽

Marina Campanini ◽

Beatriz Paixão ◽

...

Keyword(s):

Tumor Progression ◽

Wnt Pathway ◽

Target Genes ◽

Disease Recurrence ◽

Positive Staining ◽

Mrna Levels ◽

Canonical Wnt Pathway ◽

Pathway Activation ◽

Adamantinomatous Craniopharyngioma ◽

Canonical Wnt

Abstract CTNNB1 mutations and abnormal β-catenin distribution are associated with the pathogenesis of adamantinomatous craniopharyngioma (aCP). We evaluated the expression of the canonical Wnt pathway components in aCPs and its association with CTNNB1 mutations and tumor progression. Tumor samples from 14 aCP patients and normal anterior pituitary samples from eight individuals without pituitary disease were studied. Gene expression of Wnt pathway activator (WNT4), inhibitors (SFRP1, DKK3, AXIN1, and APC), transcriptional activator (TCF7), target genes (MYC, WISP2, and, CDH1), and Wnt modulator (TP53) was evaluated by qPCR. β-Catenin, MYC, and WISP2 expression was determined by immunohistochemistry (IHC). The transcription levels of all genes studied, except APC, were higher in aCPs as compared to controls and TCF7 mRNA levels correlated with CTNNB1 mutation. CDH1 mRNA was overexpressed in tumor samples of patients with disease progression in comparison to those with stable disease. β-Catenin was positive and aberrantly distributed in 11 out of 14 tumor samples. Stronger β-catenin immunostaining associated positively with tumor progression. MYC positive staining was found in 10 out of 14 cases, whereas all aCPs were negative for WISP2. Wnt pathway genes were overexpressed in aCPs harboring CTNNB1 mutations and in patients with progressive disease. Recurrence was associated with stronger staining for β-catenin. These data suggest that Wnt pathway activation contributes to the pathogenesis and prognosis of aCPs.

Download Full-text

Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway

Development ◽

10.1242/dev.127.10.2227 ◽

2000 ◽

Vol 127 (10) ◽

pp. 2227-2238 ◽

Cited By ~ 43

Author(s):

M. Tada ◽

J.C. Smith

Keyword(s):

Wnt Pathway ◽

Target Genes ◽

Dominant Negative ◽

Beta Catenin ◽

Transcription Activator ◽

Amphibian Embryo ◽

Morphogenetic Movements ◽

Canonical Wnt Pathway ◽

Canonical Wnt

Gastrulation in the amphibian embryo is driven by cells of the mesoderm. One of the genes that confers mesodermal identity in Xenopus is Brachyury (Xbra), which is required for normal gastrulation movements and ultimately for posterior mesoderm and notochord differentiation in the development of all vertebrates. Xbra is a transcription activator, and interference with transcription activation leads to an inhibition of morphogenetic movements during gastrulation. To understand this process, we have screened for downstream target genes of Brachyury (Tada, M., Casey, E., Fairclough, L. and Smith, J. C. (1998) Development 125, 3997–4006). This approach has now allowed us to isolate Xwnt11, whose expression pattern is almost identical to that of Xbra at gastrula and early neurula stages. Activation of Xwnt11 is induced in an immediate-early fashion by Xbra and its expression in vivo is abolished by a dominant-interfering form of Xbra, Xbra-En(R). Overexpression of a dominant-negative form of Xwnt11, like overexpression of Xbra-En(R), inhibits convergent extension movements. This inhibition can be rescued by Dsh, a component of the Wnt signalling pathway and also by a truncated form of Dsh which cannot signal through the canonical Wnt pathway involving GSK-3 and (beta)-catenin. Together, our results suggest that the regulation of morphogenetic movements by Xwnt11 occurs through a pathway similar to that involved in planar polarity signalling in Drosophila.

Download Full-text

Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3β: autoregulation of GSK-3β in vivo

Biochemical Journal ◽

10.1042/bj20140207 ◽

2015 ◽

Vol 466 (2) ◽

pp. 415-430 ◽

Cited By ~ 38

Author(s):

Cheril Tapia-Rojas ◽

Andreas Schüller ◽

Carolina B. Lindsay ◽

Roxana C. Ureta ◽

Cristóbal Mejías-Reyes ◽

...

Keyword(s):

Ligand Binding ◽

Wnt Pathway ◽

Target Genes ◽

Competitive Inhibition ◽

Wnt Signalling ◽

Signalling Pathway ◽

Canonical Wnt Pathway ◽

Gsk 3Β ◽

Canonical Wnt

Andrographolide activates the canonical Wnt pathway and induces the transcription of Wnt target genes through a mechanism independent of Wnt ligand binding to its receptor, by direct substrate-competitive inhibition of GSK-3.

Download Full-text