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Wnt/β-catenin signaling has come to the forefront of liver biology in recent years. This pathway regulates key pathophysiological events inherent to the liver including development, regeneration and cancer, by dictating several biological processes such as proliferation, apoptosis, differentiation, adhesion, zonation and metabolism in various cells of the liver. This review will examine the studies that have uncovered the relevant roles of Wnt/β-catenin signaling during the process of liver development. We will discuss the potential roles of Wnt/β-catenin signaling during the phases of development, including competence, hepatic induction, expansion and morphogenesis. In addition, we will discuss the role of negative and positive regulation of this pathway and how the temporal expression of Wnt/β-catenin can direct key processes during hepatic development. We will also identify some of the major deficits in the current understanding of the role of Wnt/β-catenin signaling in liver development in order to provide a perspective for future studies. Thus, this review will provide a contextual overview of the role of Wnt/β-catenin signaling during hepatic organogenesis.Key words: liver development, liver cancer, liver regeneration, Wnt signaling, proliferation, differentiationThe Wnt/β-catenin pathway is an evolutionarily well-conserved pathway that has proven to be essential to normal cellular processes such as development, growth, survival, regeneration and self-renewal.1–5 Its diverse functions also include the initiation and progression of cancer.6 In fact, one area in which this pathway has been extensively studied is in liver cancer.Mutations of Wnt/β-catenin pathway members in hepatocarcinogenesis are common. For example, 90–100% of hepatoblastomas contain mutations in adenomatous polyposis coli (APC), CTNNB1 and/or Axin1/2, which causes cytoplasmic and nuclear localization of β-catenin.7–9 Axin1 and β-catenin mutations have also been identified in approximately 25% of hepatocellular carcinomas,10–12 while overexpression of the frizzled-7 receptor13 and glycogen synthase kinase-3 (GSK-3) inactivation14 can also lead to aberrant β-catenin pathway activation. The dysregulation of this pathway in hepatic cancers makes it an attractive target for potential therapies, and experimental treatment in vivo has shown promising results. For example, inhibiting β-catenin expression by siRNA or R-Etodolac decreases proliferation and survival of human hepatoma cell lines.15,16 Since cancer recapitulates development, determining the timing of β-catenin activation during hepatogenesis will help us to better understand the inappropriate activation of this pathway in hepatocarcinogenesis.Recent work has elucidated the role of β-catenin signaling in the liver, and has highlighted its essential role in liver health and disease.17 In addition, emerging evidence suggests that this pathway plays a key role in liver organogenesis. 相似文献
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Xiaofang Wang Zhan Zhang Xianxu Zeng Jinming Wang Linlin Zhang Wanyu Song Ying Shi 《Journal of molecular histology》2018,49(3):317-327
This study aims to elucidate the mechanisms of Wnt/β-catenin signaling pathway in the development of preeclampsia (PE). The mRNA levels of Wnt1, β-catenin, c-myc and cyclinD1 were determined by real-time PCR in the placentas. Moreover, the expression levels of Wnt1, β-catenin, Dickkopf-1 (DKK1) and glycogen synthase kinase 3β (GSK-3β) proteins were detected by Western blot. Immunohistochemistry was used in placental tissue microarray to localize the expression of Wnt1, β-catenin, DKK1 proteins in the placentas of two groups. Compared with the control placentas, the mRNA levels of Wnt1, β-catenin, c-myc and cyclinD1 were decreased in the severe preeclamptic placentas. The Western blot results showed that the expression levels of Wnt1, β-catenin, and GSK-3β proteins were significantly elevated in the control group, while the expression level of DKK1 was significantly decreased. In addition, the staining intensity of Wnt1, β-catenin were weaker in the placentas of the severe PE group while the staining intensity of DKK1 was significantly stronger in the placentas of the severe PE group. Wnt/β-catenin signaling pathway may play a significant role in the pathogenesis of PE by regulating the invasion and proliferation of trophoblast. 相似文献
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The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future. 相似文献
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Jon P. Lyons Rachel K. Miller Xiaolan Zhou Gilbert Weidinger Tom Deroo Tinneke Denayer Jae-Il Park Hong Ji Ji Yeon Hong Annette Li Randall T. Moon Elizabeth A. Jones Kris Vleminckx Peter D. Vize Pierre D. McCrea 《Mechanisms of development》2009,126(3-4):142-159
The pronephric kidney controls water and electrolyte balance during early fish and amphibian embryogenesis. Many Wnt signaling components have been implicated in kidney development. Specifically, in Xenopus pronephric development as well as the murine metanephroi, the secreted glycoprotein Wnt-4 has been shown to be essential for renal tubule formation. Despite the importance of Wnt signals in kidney organogenesis, little is known of the definitive downstream signaling pathway(s) that mediate their effects. Here we report that inhibition of Wnt/β-catenin signaling within the pronephric field of Xenopus results in significant losses to kidney epithelial tubulogenesis with little or no effect on adjoining axis or somite development. We find that the requirement for Wnt/β-catenin signaling extends throughout the pronephric primordium and is essential for the development of proximal and distal tubules of the pronephros as well as for the development of the duct and glomus. Although less pronounced than effects upon later pronephric tubule differentiation, inhibition of the Wnt/β-catenin pathway decreased expression of early pronephric mesenchymal markers indicating it is also needed in early pronephric patterning. We find that upstream inhibition of Wnt/β-catenin signals in zebrafish likewise reduces pronephric epithelial tubulogenesis. We also find that exogenous activation of Wnt/β-catenin signaling within the Xenopus pronephric field results in significant tubulogenic losses. Together, we propose Wnt/β-catenin signaling is required for pronephric tubule, duct and glomus formation in Xenopus laevis, and this requirement is conserved in zebrafish pronephric tubule formation. 相似文献
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Background
Stem cells are mainly characterized by two properties: self-renewal and the potency to differentiate into diverse cell types. These processes are regulated by different growth factors including members of the Wnt protein family. Wnt proteins are secreted glycoproteins that can activate different intracellular signaling pathways.Scope of review
Here we summarize our current knowledge on the role of Wnt/β-catenin signaling with respect to these two main features of stem cells.Major conclusions
A particular focus is given on the function of Wnt signaling in embryonic stem cells. Wnt signaling can also improve reprogramming of somatic cells towards iPS cells highlighting the importance of this pathway for self-renewal and pluripotency. As an example for the role of Wnt signaling in adult stem cell behavior, we furthermore focus on intestinal stem cells located in the crypts of the small intestine.General significance
A broad knowledge about stem cell properties and the influence of intrinsic and extrinsic factors on these processes is a requirement for the use of these cells in regenerative medicine in the future or to understand cancer development in the adult. This article is part of a Special Issue entitled Biochemistry of Stem Cells. 相似文献7.
Normal heart formation requires reiterative phases of canonical Wnt/β-catenin (Wnt) signaling. Understanding the mechanisms by which Wnt signaling directs cardiomyocyte (CM) formation in vivo is critical to being able to precisely direct differentiated CMs from stem cells in vitro. Here, we investigate the roles of Wnt signaling in zebrafish CM formation using heat-shock inducible transgenes that increase and decrease Wnt signaling. We find that there are three phases during which CM formation is sensitive to modulation of Wnt signaling through the first 24 h of development. In addition to the previously recognized roles for Wnt signaling during mesoderm specification and in the pre-cardiac mesoderm, we find a previously unrecognized role during CM differentiation where Wnt signaling is necessary and sufficient to promote the differentiation of additional atrial cells. We also extend the previous studies of the roles of Wnt signaling during mesoderm specification and in pre-cardiac mesoderm. Importantly, in pre-cardiac mesoderm we define a new mechanism where Wnt signaling is sufficient to prevent CM differentiation, in contrast to a proposed role in inhibiting cardiac progenitor (CP) specification. The inability of the CPs to differentiate appears to lead to cell death through a p53/Caspase-3 independent mechanism. Together with a report for an even later role for Wnt signaling in restricting proliferation of differentiated ventricular CMs, our results indicate that during the first 3days of development in zebrafish there are four distinct phases during which CMs are sensitive to Wnt signaling. 相似文献
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The canonical Wnt/β-catenin pathway is an essential component of multiple developmental processes. To investigate the role of this pathway in the ectoderm during facial morphogenesis, we generated conditional β-catenin mouse mutants using a novel ectoderm-specific Cre recombinase transgenic line. Our results demonstrate that ablating or stabilizing β-catenin in the embryonic ectoderm causes dramatic changes in facial morphology. There are accompanying alterations in the expression of Fgf8 and Shh, key molecules that establish a signaling center critical for facial patterning, the frontonasal ectodermal zone (FEZ). These data indicate that Wnt/β-catenin signaling within the ectoderm is critical for facial development and further suggest that this pathway is an important mechanism for generating the diverse facial shapes of vertebrates during evolution. 相似文献
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Karthik Shree Harini Devaraj Ezhilarasan Uthirappan Mani 《Cell biochemistry and function》2024,42(1):e3916
Alcoholic liver disease (ALD) is one of the most common health problems worldwide, especially in developing countries caused by chronic consumption of alcohol on a daily basis. The ALD spectrum is initiated with the early stages of alcoholic fatty liver (steatosis), progressing to alcoholic steatohepatitis, followed by the later stages of fibrosis and in some cases, cirrhosis and hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling required for healthy liver development, function, and regeneration is found to be aberrated in ALD, attributed to its progression. This review is to elucidate the association of Wnt/β-catenin signaling with various stages of ALD progression. Alcohol causes downregulation of Wnt/β-catenin signaling components and thereby suppressing the pathway. Reports have been published that aberrated Wnt/β-catenin signaling, especially the absence of β-catenin, results in decreased alcohol metabolism, causing steatosis followed by steatohepatitis via lipid accumulation, lipid peroxidation, liver injury, increased oxidative stress and apoptosis of hepatocytes, contributing to the advancement of ALD. Contrastingly, the progression of later stages of ALD like fibrosis and HCC depends on the increased activation of Wnt/β-catenin signaling and its components. Existing studies reveal the varied expression of Wnt/β-catenin signaling in ALD. However, the dual role of the Wnt/β-catenin pathway in earlier and later stages of ALD is not clear. Therefore, studies on the Wnt/β-catenin pathway and its components in various manifestations of ALD might provide insight in targeting the Wnt/β-catenin pathway in ALD treatment. 相似文献
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Yajing Wang Zhaorui Sun Xuefeng Qiu Yan Li Xiaodong Han 《Biochemical and biophysical research communications》2009,390(4):1309-1816
Bone marrow-derived mesenchymal stem cells (MSCs) have been demonstrated to be able to differentiate into epithelial lineage, but the precise mechanisms controlling this process are unclear. Our aim is to explore the roles of Wnt/β-catenin in the epithelial differentiation of MSCs. Using indirect co-culture of rat MSCs with rat airway epithelial cells (RTE), MSCs expressed several airway epithelial markers (cytokeratin 18, tight junction protein occudin, cystic fibrosis transmembrance regulator). The protein levels of some important members in Wnt/β-catenin signaling were determined, suggested down-regulation of Wnt/β-catenin with epithelial differentiation of MSCs. Furthermore, Wnt3α can inhibit the epithelial differentiation of MSCs. A loss of β-catenin induced by Dickkopf-1 can enhance MSCs differentiation into epithelial cells. Lithium chloride transiently activated β-catenin expression and subsequently decreased β-catenin level and at last inhibited MSCs to differentiate into airway epithelium. Taken together, our study indicated that RTE cells can trigger epithelial differentiation of MSCs. Blocking Wnt/β-catenin signaling may promote MSCs to differentiate towards airway epithelial cells. 相似文献
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Hidekazu Iioka 《FEBS letters》2009,583(4):627-632
The Wnt family of secreted ligands plays critical roles during embryonic development and tumorigenesis. Here we show that Kaiso, a dual specific DNA-binding protein, functions as a bimodal regulator of canonical Wnt signaling. Loss-of-function analysis of Kaiso abrogated Wnt-mediated reporter activity and axis duplication, whereas gain-of-function analysis of Kaiso dose-dependently resulted in synergistic and suppressive effects. Our analyses further suggest Kaiso can regulate TCF/LEF1-activity for these effects via modulating HDAC1 and β-catenin-complex formation. Our studies together provide insights into why Kaiso null mice display resistance to intestinal tumors when crossed onto an ApcMin/+ background.
Stuctured summary
MINT-6823807: HDAC1 (uniprotkb:Q13547) physically interacts (MI:0218) with beta catenin (uniprotkb:P35222) by anti tag coimmunoprecipitation (MI:0007)MINT-6823820: axin (uniprotkb:O15169) physically interacts (MI:0218) with beta catenin (uniprotkb:P35222) by anti tag coimmunoprecipitation (MI:0007) 相似文献15.
Nina Rawal Paola Sacchetti Bita Sehat Ernest Arenas 《Biochemical and biophysical research communications》2009,388(3):473-1042
Parkinson’s disease (PD) is caused by degeneration of the dopaminergic (DA) neurons of the substantia nigra but the molecular mechanisms underlying the degenerative process remain elusive. Several reports suggest that cell cycle deregulation in post-mitotic neurons could lead to neuronal cell death. We now show that Parkin, an E3 ubiquitin ligase linked to familial PD, regulates β-catenin protein levels in vivo. Stabilization of β-catenin in differentiated primary ventral midbrain neurons results in increased levels of cyclin E and proliferation, followed by increased levels of cleaved PARP and loss of DA neurons. Wnt3a signaling also causes death of post-mitotic DA neurons in parkin null animals, suggesting that both increased stabilization and decreased degradation of β-catenin results in DA cell death. These findings demonstrate a novel regulation of Wnt signaling by Parkin and suggest that Parkin protects DA neurons against excessive Wnt signaling and β-catenin-induced cell death. 相似文献
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Anjen Chenn 《Organogenesis》2008,4(2):76-80
The cerebral cortex is the multilayered sheet of neurons that underlies our highest cognitive abilities. Canonical Wnt/β-catenin signaling has well-known activities in tissue patterning in regulating rostral-caudal and medial-lateral patterning in the developing cortex. In addition, recent studies suggest that Wnt/β-catenin signaling also plays important roles in establishing the radial inside to outside organization of the cerebral cortex. Different Wnts, Wnt receptors and inhibitors are expressed in overlapping radial compartments of the cerebral cortex, and in vivo functional studies have provided evidence for Wnt/β-catenin regulation of neural precursor self-renewal, laminar fate determination and establishing or stabilizing the patterns of neuronal communication of cortical neurons. Wnt/β-catenin alterations have been observed in human brain tumors, and understanding its many diverse functions during normal neural development may provide greater insight into the mechanisms underlying the development and progression of neural tumors.Key words: cerebral cortex, neural stem cell, neural precursor, ventricular zone, laminar fate, regional specification, radial patterning 相似文献
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Fernández-Torres Javier Zamudio-Cuevas Yessica López-Reyes Alberto Garrido-Rodríguez Daniela Martínez-Flores Karina Lozada Carlos Alberto Muñóz-Valle José Francisco Oregon-Romero Edith Martínez-Nava Gabriela Angélica 《Molecular biology reports》2018,45(5):1089-1098
Molecular Biology Reports - This study was designed to investigate whether genetic polymorphisms of the Wnt/β-catenin signaling pathway and its interactions are involved in the development of... 相似文献
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Wnt/β-catenin signaling plays an important role not only in cancer, but also in cancer stem cells. In this study, we found that β-catenin and OCT-4 was highly expressed in cisplatin (DDP) selected A549 cells. Stimulating A549 cells with lithium chloride (LiCl) resulted in accumulation of β-catenin and up-regulation of a typical Wnt target gene cyclin D1. This stimulation also significantly enhanced proliferation, clone formation, migration and drug resistance abilities in A549 cells. Moreover, the up-regulation of OCT-4, a stem cell marker, was observed through real-time PCR and Western blotting. In a reverse approach, we inhibited Wnt signaling by knocking down the expression of β-catenin using RNA interference technology. This inhibition resulted in down-regulation of the Wnt target gene cyclin D1 as well as the proliferation, clone formation, migration and drug resistance abilities. Meanwhile, the expression of OCT-4 was reduced after the inhibition of Wnt/β-catenin signaling. Taken together, our study provides strong evidence that canonical Wnt signaling plays an important role in lung cancer stem cell properties, and it also regulates OCT-4, a lung cancer stem cell marker. 相似文献