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24 pages, 1451 KiB

Open AccessArticle

Diverse LEF/TCF Expression in Human Colorectal Cancer Correlates with Altered Wnt-Regulated Transcriptome in a Meta-Analysis of Patient Biopsies

by Claus-Dieter Mayer, Soizick Magon de La Giclais, Fozan Alsehly and Stefan Hoppler

Genes 2020, 11(5), 538; https://doi.org/10.3390/genes11050538 - 11 May 2020

Cited by 13 | Viewed by 3818

Abstract

Aberrantly activated Wnt signaling causes cellular transformation that can lead to human colorectal cancer. Wnt signaling is mediated by Lymphoid Enhancer Factor/T-Cell Factor (LEF/TCF) DNA-binding factors. Here we investigate whether altered LEF/TCF expression is conserved in human colorectal tumor sample and [...] Read more.

Aberrantly activated Wnt signaling causes cellular transformation that can lead to human colorectal cancer. Wnt signaling is mediated by Lymphoid Enhancer Factor/T-Cell Factor (LEF/TCF) DNA-binding factors. Here we investigate whether altered LEF/TCF expression is conserved in human colorectal tumor sample and may potentially be correlated with indicators of cancer progression. We carried out a meta-analysis of carefully selected publicly available gene expression data sets with paired tumor biopsy and adjacent matched normal tissues from colorectal cancer patients. Our meta-analysis confirms that among the four human LEF/TCF genes, LEF1 and TCF7 are preferentially expressed in tumor biopsies, while TCF7L2 and TCF7L1 in normal control tissue. We also confirm positive correlation of LEF1 and TCF7 expression with hallmarks of active Wnt signaling (i.e., AXIN2 and LGR5). We are able to correlate differential LEF/TCF gene expression with distinct transcriptomes associated with cell adhesion, extracellular matrix organization, and Wnt receptor feedback regulation. We demonstrate here in human colorectal tumor sample correlation of altered LEF/TCF gene expression with quantitatively and qualitatively different transcriptomes, suggesting LEF/TCF-specific transcriptional regulation of Wnt target genes relevant for cancer progression and survival. This bioinformatics analysis provides a foundation for future more detailed, functional, and molecular analyses aimed at dissecting such functional differences. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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Graphical abstract
Full article ">Figure 1
Forest plots of gene expression of all four LEF/TCF genes (A): TCF7, (B): LEF1, (C): TCF7L1, (D): TCF7L2, and (E): AXIN2, (F): DICKKOPF-1 (DKK1), (G): FZD7, and (H): LGR5, from six selected studies. Columns from left to right indicate: accession no. of study (with GSE20842 [<a href="#B27-genes-11-00538" class="html-bibr">27</a>] separated between kras-positive and kras-mutant samples); number of patients in individual studies; horizontal segments indicate the standardized mean difference between tumor and normal, and their confidence interval, with the size of the square dot being proportional with the weight of the study in the meta-analysis using a ‘random effects’ model. The corresponding values are written in the column on the right: weight of the individual study in percent as part of the meta-analysis; standardized mean difference; and in square brackets confidence interval. The red polygon in the bottom of each plot shows the summary estimate based on the random-effect model. Values to the left of the midline indicated higher expression in the control relative to the tumor sample, e.g., see AXIN2 and LGR5. Individual studies with small sample size (i.e., few patients) as expected often have larger confidence intervals (therefore less reliability, e.g., see TCF7 and LEF1 data for GSE46622 study), but in the meta-analysis (in red) much tighter confidence intervals (therefore higher reliability). Note that, among the four LEF/TCF genes, TCF7, LEF1, are expressed higher, while TCF7L1, TCF7L2 lower in tumor tissue. Full article ">Figure 2
Correlation plot matrix of relative gene expression between eight selected genes in six selected studies (A–N), with normal control (A, C, E, G, I, K, M) separated from tumor sample (B, D, F, H, J, L, N), and additionally for the GSE20842 [<a href="#B27-genes-11-00538" class="html-bibr">27</a>] between kras-mutant (“mut”) samples (C, D) and kras-positive (“wild” as in wildtype) samples (E, F). Blue dots indicate positive and red dots negative correlation. The size of the circle and the intensity of the color is proportional to the correlation coefficient; therefore, as an internal control, expected diagonal series of large blue dots where expression of genes is compared to the expression of the same gene). Missing values in GSE46622 [<a href="#B30-genes-11-00538" class="html-bibr">30</a>] is due to low value data for LEF1 in this study. Note positive correlation between AXIN2 expression and LGR5, TCF7 and LEF1 expression, yet negative correlation with TCF7L1 expression, while TCF7L1 and FZD7 expression are positively correlated, though clearly much more so in normal control tissue than in tumor. In contrast, the correlation between AXIN2 and TCF7 expression is clearly more robust in tumor compared to normal tissue. Interestingly, the unearthed correlation between TCF7L1 and FZD7 expression appears to be dependent on wild-type kRAS in the tumor (compare D with F, yet not in normal control C). Full article ">Figure 3
Correlation of transcript expression between eight selected genes (TCF7, LEF1, TCF7L1, TCF7L2, AXIN2, DKK1, FZD7 and LGR5) in normal control tissue (A), in tumor tissue (B), and when analyzed combined in normal and tumor tissue (C) (negative numbers and graded red highlighting indicates negative correlation; positive numbers and graded green highlighting positive correlation). (D) Mean difference between normal and tumor tissue of correlation of transcript expression between eight selected genes (red highlighting with positive numbers indicates reduced negative correlation in tumor tissue; green highlighting with negative numbers indicates reduced, with positive numbers increased, positive correlation in tumor tissue; yellow highlighting with positive numbers indicates a switch from negative to positive, and with negative numbers to negative, correlation in tumor tissue. Note generally reduced correlations in tumor tissue; particularly note, reduced positive correlation between TCF7 and LEF1, between TCF7 and LGR5, and between TCF7L1 and FZD7 expression; and reduced negative correlation between AXIN2 and TCF7L1 expression. However, also note exceptional increased positive correlation between AXIN2 and TCF7 in tumor tissue. Full article ">

15 pages, 2602 KiB

Open AccessCommunication

Vulpinic Acid Controls Stem Cell Fate toward Osteogenesis and Adipogenesis

by Sang Ah Yi, Ki Hong Nam, Sil Kim, Hae Min So, Rhim Ryoo, Jeung-Whan Han, Ki Hyun Kim and Jaecheol Lee

Genes 2020, 11(1), 18; https://doi.org/10.3390/genes11010018 - 23 Dec 2019

Cited by 7 | Viewed by 3460

Abstract

Vulpinic acid, a naturally occurring methyl ester of pulvinic acid, has been reported to exert anti-fungal, anti-cancer, and anti-oxidative effects. However, its metabolic action has not been implicated yet. Here, we show that vulpinic acid derived from a mushroom, Pulveroboletus ravenelii controls the [...] Read more.

Vulpinic acid, a naturally occurring methyl ester of pulvinic acid, has been reported to exert anti-fungal, anti-cancer, and anti-oxidative effects. However, its metabolic action has not been implicated yet. Here, we show that vulpinic acid derived from a mushroom, Pulveroboletus ravenelii controls the cell fate of mesenchymal stem cells and preadipocytes by inducing the acetylation of histone H3 and α-tubulin, respectively. The treatment of 10T1/2 mesenchymal stem cells with vulpinic acid increased the expression of Wnt6, Wnt10a, and Wnt10b, which led to osteogenesis inhibiting the adipogenic lineage commitment, through the upregulation of H3 acetylation. By contrast, treatment with vulpinic acid promoted the terminal differentiation of 3T3-L1 preadipocytes into mature adipocytes. In this process, the increase in acetylated tubulin was accompanied, while acetylated H3 was not altered. As excessive generation of adipocytes occurs, the accumulation of lipid drops was not concentrated, but dispersed into a number of adipocytes. Consistently, the expressions of lipolytic genes were upregulated and inflammatory factors were downregulated in adipocytes exposed to vulpinic acid during adipogenesis. These findings reveal the multiple actions of vulpinic acid in two stages of differentiation, promoting the osteogenesis of mesenchymal stem cells and decreasing hypertrophic adipocytes, which can provide experimental evidence for the novel metabolic advantages of vulpinic acid. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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13 pages, 1303 KiB

Open AccessArticle

Wnt-11 Expression Promotes Invasiveness and Correlates with Survival in Human Pancreatic Ductal Adeno Carcinoma

by Dafydd A. Dart, Damla E Arisan, Sioned Owen, Chunyi Hao, Wen G. Jiang and Pinar Uysal-Onganer

Genes 2019, 10(11), 921; https://doi.org/10.3390/genes10110921 - 11 Nov 2019

Cited by 11 | Viewed by 3355

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, proving difficult to manage clinically. Wnt-11, a developmentally regulated gene producing a secreted protein, has been associated with various carcinomas but has not previously been studied in PDAC. The present study [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, proving difficult to manage clinically. Wnt-11, a developmentally regulated gene producing a secreted protein, has been associated with various carcinomas but has not previously been studied in PDAC. The present study aimed to elucidate these aspects first in vitro and then in a clinical setting in vivo. Molecular analyses of Wnt-11 expression as well as other biomarkers involved qRT-PCR, RNA-seq and siRNA. Proliferation was measured by MTT; invasiveness was quantified by Boyden chamber (Matrigel) assay. Wnt-11 mRNA was present in three different human PDAC cell lines. Wnt-11 loss affected epithelial-mesenchymal transition and expression of neuronal and stemness biomarkers associated with metastasis. Indeed, silencing Wnt-11 in Panc-1 cells significantly inhibited their Matrigel invasiveness without affecting their proliferative activity. Consistently with the in vitro data, human biopsies of PDAC showed significantly higher Wnt-11 mRNA levels compared with matched adjacent tissues. Expression was significantly upregulated during PDAC progression (TNM stage I to II) and maintained (TNM stages III and IV). Wnt-11 is expressed in PDAC in vitro and in vivo and plays a significant role in the pathophysiology of the disease; this evidence leads to the conclusion that Wnt-11 could serve as a novel, functional biomarker PDAC. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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Figure 1
Wnt-11 mRNA relative expression profile in Bx-PC3, Panc-1 and MiaPaca-2 cells, and Wnt-11 siRNA on Panc-1 cells. (A) Real-time PCR result of Wnt-11 relative mRNA expression. Data are plotted as fold-differences relative to the Bx-PC3 cell Wnt-11 mRNA expression level after normalising with housekeeping gene (RPII) level. Panc-1 cells express the highest amount of Wnt-11 mRNA (folds more than Bx–PC3; n = 6; p < 0.01) among three pancreatic cancer cell lines and Wnt-11 siRNA reduces the expression 4.52-fold (light grey bar; n = 6; p = 0.011). All data were analysed as means ± standard errors. Statistical significance was determined using Student’s t-test or ANOVA with Newman–Keuls post-hoc analysis were used, as appropriate. (B,C) Immunostaining for Wnt-11 (green) and To-Pro (blue) in Panc-1 cells transfected with Wnt-11siRNA. (B) Control. (C) Wnt-11 siRNA for 48 hours. Scale bar, 20 µm (applicable to both panels). Full article ">Figure 2
Wnt-11 promotes epithelial-mesenchymal transition (EMT) and neuronal differentiation in Panc-1 cells line. (A) qRT-PCR for NSE, NeuroD, Hes6 and Nanog relative mRNA expressions after transfection of Panc-1 cells either with scrambled or Wnt-11 siRNA after 48 hours. Wnt-11 siRNA. (B) qRT-PCR for EMT markers; Ecad, Snail, Vim and Twist relative mRNA expressions after transfection of Panc-1 cells either with scrambled or Wnt-11 siRNA after 48 hours. NSE, NeuroD, Hes6 and Nanog mRNA expressions and they were reduced after silencing Wnt-11 (53%, 89%, 51.5% and 94% respectively; n = 6; p < 0.05 for all). Wnt-11 siRNA increased Ecad mRNA expression 5.29-fold in Panc-1 cells (n = 6; p = 0.02). Other EMT markers, such as Snail, Vim and Twist expressed in Panc-1 and MiaPaca-2 cells and this expression was reduced by Wnt-11 siRNA in Panc-1 cells (Fig 2B; min 70% reduction for all, n = 6; p < 0.05). Statistical significance was determined using Student’s t-test and ANOVA were used. Full article ">Figure 3
Functional evidence for Wnt-11-induced reduction of Matrigel invasion on Panc-1 cell lines. Panc-1 cells were transfected for 72 hours with control or Wnt-11 siRNAs, plated on Matrigel coated transwell filters and the extent of invasion determined after 16 hours. (A) Wnt-11 siRNA decreased invasion by 23% (n = 3; p = 0.02). The results are plotted as Invasion Index (InvI, %), which is the percentage of invaded cells compared to the total number of cells seeded. (B) The total cell number/proliferation did not change during the course of the experiment (n = 3; p > 0.05). All data were analysed as means ± standard errors. Full article ">Figure 4
Clinical evidence that Wnt-11 was significantly upregulated in a cohort of pancreatic tumour samples. (A) In total, 111 pairs of tumour and adjacent control tissues were studied and Wnt-11 expression (relative) appeared to be increased in the tumour tissue compared to adjacent normal tissues (p = 0.02). (B) A high level of Wnt-11 expression (relative) was found in patients classified according to T staging (p < 0.05 for T1 vs T2 or T3 or T4; T2 vs T3 or T3 vs T4 p > 0.05). All data were analysed as means ± standard errors. Full article ">Figure 5
A survival curve gained from Human Protein Atlas shows that a high expression of Wnt-11 reduces cumulative survival of PDAC. (p = 0.02). A low expression (n = 121). High expression (n = 55). 5-year survival high 26%; 5-year survival low 31%. [<a href="#B34-genes-10-00921" class="html-bibr">34</a>]. Kaplan–Meier survival estimators examined the prognosis of each group of patients, and the survival outcomes of the two groups were compared. Bylog ranktests. <a href="https://www.proteinatlas.org/ENSG00000085741WNT11/pathology/pancreatic" target="_blank">https://www.proteinatlas.org/ENSG00000085741WNT11/pathology/pancreatic</a> + cancer # Location. Accessed on 22 October 2019. Full article ">

Review

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20 pages, 2325 KiB

Open AccessReview

The Canonical Wnt Pathway as a Key Regulator in Liver Development, Differentiation and Homeostatic Renewal

by Sebastian L. Wild, Aya Elghajiji, Carmen Grimaldos Rodriguez, Stephen D. Weston, Zoë D. Burke and David Tosh

Genes 2020, 11(10), 1163; https://doi.org/10.3390/genes11101163 - 30 Sep 2020

Cited by 17 | Viewed by 8301

Abstract

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of [...] Read more.

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of the gut tube, the primitive precursor of liver. In adults, the Wnt/β-catenin pathway is increasingly recognised as an important regulator of metabolic zonation, homeostatic renewal and regeneration in response to injury throughout the liver. Herein, we review recent developments relating to the key role of the pathway in the patterning and fate specification of the liver, in the directed differentiation of pluripotent stem cells into hepatocytes and in governing proliferation and zonation in the adult liver. We pay particular attention to recent contributions to the controversy surrounding homeostatic renewal and proliferation in response to injury. Furthermore, we discuss how crosstalk between the Wnt/β-catenin and Hedgehog (Hh) and hypoxia inducible factor (HIF) pathways works to maintain liver homeostasis. Advancing our understanding of this pathway will benefit our ability to model disease, screen drugs and generate tissue and organ replacements for regenerative medicine. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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Figure 1
Summary of Wnt/β-catenin, Hedgehog and hypoxia inducible factor (HIF) pathways and their downstream mediators in the liver. (A) Active Wnt/β-catenin signalling. Wnt2 and Wnt9b secreted from central vein endothelial cell complex with LRP5/6 and FZD receptors. The β-catenin destruction complex is prevented from assembling allowing cytoplasmic accumulation of β-catenin which in turn permits β-catenin’s translocation to the nucleus. β-catenin then complexes with co-factors including CREB binding protein (CBP), TCF/LEF, B-cell lymphoma 9 (BCL-9) and pygopus protein (Pygo) to promote transcription of genes under β-catenin transcriptional control including c-Myc, CyclinD1, GS, aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR). (B) Active HIF1 signalling. Constitutively expressed HIF1α subunits avoid ubiquitin ligase, HIF prolyl hydroxylase (PHD) and VHL (von Hippel Lindau) facilitated proteasomal degradation when PHD is inactivated by low pO2. HIF1α subunits are then free to translocate to the nucleus where they dimerise with aryl hydrocarbon receptor nuclear translocator (ARNT) beta subunits to form HIF1 which is then able to bind to HIFresponse elements (HREs) and affect transcription of genes including vascular endothelial growth factor (VEGF), plasminogen activator inhibitor 1 (PAI1), P4HA2, HO1, erythropoietin, ceruloplasmin glucokinase and bone morphogenic protein (BMP). (C) Active Hh signalling. Hh ligands bind and inhibit their cognate receptor patched (PTCH). PTCH is no longer able to inhibit the G-protein coupled receptor smoothened (SMO), and SMO is phosphorylated by CKI and GPRK2 causing translocation from intracellular endosomes to the plasma membrane of primary cilia. Gli proteins (Gli1, Gli2, Gli3) can then escape association with suppressor of fused homolog (SUFU) and phosphorylation by GSK3β, protein kinase A (PKA), CKI and resulting in proteasomal degradation. It is then free to translocate to the nucleus to effect transcription of Hh target genes including VEGF, angiopoietin 1 and 2; Snail, Nanog, SOX2 and 9; Twist2, α-SMA and vimentin. Full article ">Figure 2
Structural and functional zonation in the adult liver. (A) The liver receives oxygenated blood from the heart via the hepatic artery (red; 25%) and deoxygenated blood via the portal vein (blue; 75%). Blood drains via the inferior vena cava (purple). Bile drains from the liver and gallbladder via the common hepatic duct (green). (B) Liver lobules are roughly hexagonal. The portal triads comprise the portal vein, hepatic artery and bile duct and are found at each vertex surrounding a central vein. (C) The acinus is divided into 3 zones: periportal, intermediate and perivenous. APC and carbamoyl phosphate synthase 1 (CPS1) are expressed throughout the periportal and intermediate zones in a mutually exclusive relationship with glutamine synthetase (GS) which is expressed only in the last 1–2 layers of hepatocytes in the perivenous zone as result of the transcriptional activity of nuclear β-catenin. Wnt/β-catenin signalling is, therefore, largely restricted to the perivenous zone. Oxygen (O2) concentration (pO2) decreases as blood moves through the acinus and is lowest in the perivenous zone. HIF activity is highest in the perivenous region. Hh ligands are secreted by periportal endothelial cells. (D) The acinus comprises a sinusoid connecting the hepatic artery and portal vein with the central vein. Oxygenated blood from the hepatic artery mixes with deoxygenated blood from the portal vein as it flows towards the central vein. Stellate cells and Kupffer cells are present throughout the endothelial sinusoid. Bile secreted from the apical membrane of hepatocytes drains into the canal of Herring which empties into the bile duct. The basolateral membranes of hepatocytes line the sinusoid and project into the space of Disse where proteins and metabolites are exchanged. Stellate cells are found in the space of Disse, a cavity which separates hepatocytes from the sinusoidal endothelial cells. Kupffer cells, the resident macrophage cell, are present within the endothelial sinusoid. Full article ">Figure 3
Role of Wnt/β-catenin signalling in gut tube patterning. After gastrulation, the definitive endoderm (DE) forms into the primitive gut tube along the anterior–posterior axis. This gives rise to the foregut, midgut and hindgut domains. Wnt/β-catenin signalling acts by inducing midgut and hindgut development in the posterior axis. Foregut formation occurs when Wnt antagonists secreted from the anterior endoderm suppress Wnt/β-catenin signalling, allowing for subsequent liver development. Full article ">

18 pages, 1322 KiB

Open AccessReview

Wnt/β-catenin Signaling in Tissue Self-Organization

by Kelvin W. Pond, Konstantin Doubrovinski and Curtis A. Thorne

Genes 2020, 11(8), 939; https://doi.org/10.3390/genes11080939 - 14 Aug 2020

Cited by 23 | Viewed by 5849

Abstract

Across metazoans, animal body structures and tissues exist in robust patterns that arise seemingly out of stochasticity of a few early cells in the embryo. These patterns ensure proper tissue form and function during early embryogenesis, development, homeostasis, and regeneration. Fundamental questions are [...] Read more.

Across metazoans, animal body structures and tissues exist in robust patterns that arise seemingly out of stochasticity of a few early cells in the embryo. These patterns ensure proper tissue form and function during early embryogenesis, development, homeostasis, and regeneration. Fundamental questions are how these patterns are generated and maintained during tissue homeostasis and regeneration. Though fascinating scientists for generations, these ideas remain poorly understood. Today, it is apparent that the Wnt/β-catenin pathway plays a central role in tissue patterning. Wnt proteins are small diffusible morphogens which are essential for cell type specification and patterning of tissues. In this review, we highlight several mechanisms described where the spatial properties of Wnt/β-catenin signaling are controlled, allowing them to work in combination with other diffusible molecules to control tissue patterning. We discuss examples of this self-patterning behavior during development and adult tissues’ maintenance. The combination of new physiological culture systems, mathematical approaches, and synthetic biology will continue to fuel discoveries about how tissues are patterned. These insights are critical for understanding the intricate interplay of core patterning signals and how they become disrupted in disease. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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Figure 1
General model for the Wnt/β-catenin signaling pathway and its regulation by the destruction complex. The destruction complex: Axin, Adenomatous polyposis coli (APC), casein kinase 1 α (CK1α), glycogen synthase kinase 3 (GSK3), protein phosphatase 2A (PP2a), and the ubiquitin ligase βTrCP. Membrane receptors: Frizzled (FZD) and low-density lipoprotein receptor-related protein 6 (Lrp6). Dishevelled (Dvl) T-cell factor (TCF). Full article ">Figure 2
Wnt/β-catenin signaling in tissue self-organization. Two main categories are shown, Embryogenesis/Development (top) and Regeneration/Homeostasis (bottom). The categories were partitioned due to reversibility. Development of the embryo and body axis as well as appendage development are irreversible and temporally regulated patterning processes. Uniquely, regeneration and homeostasis are ongoing processes that an organism must call upon when needed. These processes have a greater need to be autonomous and could not withstand removal of a morphogen source unless there was a mechanism in place for sensing and replacing a missing niche. Full article ">Figure 3
Examples of Wnt/β-catenin-dependent Reaction-Diffusion (RD) mechanisms implicated in tissue patterning. (A) Over time, a short-range activator and a long-range inhibitor interact to form local morphogen concentrations in patterns. (B) Basic model for the RD activator/inhibitor pair. (C) Examples of Wnt-driven patterning driven by RD mechanisms. Although the morphogen pairs/triplets and their mechanisms of control varies, the basic activator/inhibitor concepts are maintained and predicted by mathematical modeling. Patterning images C1–C4 were adapted from References [<a href="#B37-genes-11-00939" class="html-bibr">37</a>,<a href="#B46-genes-11-00939" class="html-bibr">46</a>,<a href="#B47-genes-11-00939" class="html-bibr">47</a>,<a href="#B48-genes-11-00939" class="html-bibr">48</a>]. Full article ">

11 pages, 1677 KiB

Open AccessReview

Nuclear Regulation of Wnt/β-Catenin Signaling: It’s a Complex Situation

by Christin C. Anthony, David J. Robbins, Yashi Ahmed and Ethan Lee

Genes 2020, 11(8), 886; https://doi.org/10.3390/genes11080886 - 4 Aug 2020

Cited by 79 | Viewed by 7827

Abstract

Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. [...] Read more.

Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway—nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus. We then focus on the mechanism of action of the major nuclear proteins implicated in driving gene transcription. Finally, we explore the concept of a nuclear Wnt enhanceosome and propose a modified model that describes the necessary components for the transcription of Wnt target genes. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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25 pages, 1238 KiB

Open AccessReview

Glia and Neural Stem and Progenitor Cells of the Healthy and Ischemic Brain: The Workplace for the Wnt Signaling Pathway

by Tomas Knotek, Lucie Janeckova, Jan Kriska, Vladimir Korinek and Miroslava Anderova

Genes 2020, 11(7), 804; https://doi.org/10.3390/genes11070804 - 16 Jul 2020

Cited by 17 | Viewed by 4619

Abstract

Wnt signaling plays an important role in the self-renewal, fate-commitment and survival of the neural stem/progenitor cells (NS/PCs) of the adult central nervous system (CNS). Ischemic stroke impairs the proper functioning of the CNS and, therefore, active Wnt signaling may prevent, ameliorate, or [...] Read more.

Wnt signaling plays an important role in the self-renewal, fate-commitment and survival of the neural stem/progenitor cells (NS/PCs) of the adult central nervous system (CNS). Ischemic stroke impairs the proper functioning of the CNS and, therefore, active Wnt signaling may prevent, ameliorate, or even reverse the negative effects of ischemic brain injury. In this review, we provide the current knowledge of Wnt signaling in the adult CNS, its status in diverse cell types, and the Wnt pathway’s impact on the properties of NS/PCs and glial cells in the context of ischemic injury. Finally, we summarize promising strategies that might be considered for stroke therapy, and we outline possible future directions of the field. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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Figure 1
Overview of the canonical and non-canonical Wnt signaling pathways. (A) β-catenin-dependent signaling is activated by binding of a canonical Wnt ligand to the frizzled (FZD) receptor and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor. Subsequently, β-catenin is released from the destruction complex and translocated to the nucleus, where it forms a complex with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins in order to activate transcription of the Wnt-responsive genes; (B) Activation of the non-canonical—β-catenin-independent—Wnt signaling branches influences cell properties and results in transcription of alternative Wnt target genes. In addition, in some cells non-canonical signaling inhibits β-catenin-mediated transcription. A more detailed description of the pathways is given in the text. Abbreviations: AP1, activator protein 1; APC, adenomatous polyposis coli; AXIN, axis inhibition; β-CAT, β-catenin; β-TrCP, β-transducin repeats-containing protein; C-JUN, transcription factor C-JUN; Ca2+, calcium; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CDC42, GTPase CDC42; CK1, casein kinase 1; DAAM1, DVL-associated activator of morphogenesis 1; DAG, diacylglycerol; DKK, dickkopf; DVL, dishevelled; ER, endoplasmic reticulum; GSK3β, glycogen synthase kinase 3β; IP3, inositol trisphosphate; JNK, c-Jun N-terminal kinase; NFAT, nuclear factor of activated T-cells; NLK, nemo-like kinase; P, phosphorylation; PCP, planar cell polarity; PKC, protein kinase C; PLC, phospholipase C; RAC1, Rac family small GTPase 1; RhoA, Ras homolog family member A; ROCK, Rho-associated kinase; ROR, receptor tyrosine kinase ROR; RYK, receptor tyrosine kinase RYK; sFRP, secreted FZD-related proteins; TLE, transducin-like enhancer of split; Ub, ubiquitination; WIF, Wnt inhibitory factor. Full article ">Figure 2
Neurogenic niches of the adult mammalian brain. Schematic diagrams illustrating the main cellular components within the neurogenic niche in the (A) subventricular zone (SVZ) of the lateral ventricles (LVs) and (B) dentate gyrus (DG) of the hippocampus (HIP) containing the neurogenic niche in the subgranular zone (SGZ), and representative immunofluorescence images of the corresponding regions showing the main markers of cell types indicated in the illustrated schemes. The neuronal lineage in both compartments is represented by neural stem cells (NSCs), neural progenitor cells (NPCs) and migrating neuroblasts. In addition, neuronal maturation is shown in the granule cell layer (GCL) adjacent to the SGZ. Glial cells, represented by astrocytes and neuron-glial antigen 2 (NG2)-positive glia in both regions, and by ependymal cells constituting the ventricular wall (VW) of the LVs, release Wnt ligands (in red color) in order to activate quiescent NSCs and mediate their proliferation/differentiation. Glial fibrillary acidic protein (GFAP) represents NSCs and a subpopulation of astrocytes; proliferating cell nuclear antigen (PCNA) marks proliferating progenitors; doublecortin (DCX)-positive cells identify both neuroblasts and immature neurons; NG2 is present in NG2 glia; 4′,6-diamidino-2-phenylindole (DAPI) stains cell nuclei. Note that the magnified field and DG histology in panel B are rotated approximately 90° counterclockwise compared to the scheme of the frontal section. Scale bar: 15 µm. Abbreviations: CC, corpus callosum; CTX, cortex; STR, striatum. Full article ">

19 pages, 1114 KiB

Open AccessReview

The Role of Wnt Signalling in Chronic Kidney Disease (CKD)

by Soniya A. Malik, Kavindiya Modarage and Paraskevi Goggolidou

Genes 2020, 11(5), 496; https://doi.org/10.3390/genes11050496 - 30 Apr 2020

Cited by 23 | Viewed by 4985

Abstract

Chronic kidney disease (CKD) encompasses a group of diverse diseases that are associated with accumulating kidney damage and a decline in glomerular filtration rate (GFR). These conditions can be of an acquired or genetic nature and, in many cases, interactions between genetics and [...] Read more.

Chronic kidney disease (CKD) encompasses a group of diverse diseases that are associated with accumulating kidney damage and a decline in glomerular filtration rate (GFR). These conditions can be of an acquired or genetic nature and, in many cases, interactions between genetics and the environment also play a role in disease manifestation and severity. In this review, we focus on genetically inherited chronic kidney diseases and dissect the links between canonical and non-canonical Wnt signalling, and this umbrella of conditions that result in kidney damage. Most of the current evidence on the role of Wnt signalling in CKD is gathered from studies in polycystic kidney disease (PKD) and nephronophthisis (NPHP) and reveals the involvement of β-catenin. Nevertheless, recent findings have also linked planar cell polarity (PCP) signalling to CKD, with further studies being required to fully understand the links and molecular mechanisms. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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