Wnt/β-catenin signaling pathway in severe preeclampsia

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.     

Therapeutic potential of targeting the Wnt/β-catenin pathway in the treatment of pancreatic cancer

The Wnt/β-catenin pathway is an important, dysregulated pathway in several tumor types, including pancreatic ductal adenocarcinoma. Although the activation of this pathway is an important component of normal development, its aberrant activation resulting from activating or inactivating mutations in the CTNNB1 gene locus, or in the negative regulators AXIN and APC involving stabilization of β-catenin, and activation of target genes leads to a more aggressive phenotype, suggesting its potential value as a therapeutic target in the treatment of pancreatic ductal adenocarcinoma. A number of small molecule and biologic agents have now been developed for targeting this pathway. This review summarizes the current knowledge about the therapeutic potential of targeting the Wnt pathway with particular emphasis on preclinical/clinical studies in the treatment of pancreatic ductal adenocarcinoma.     

Gene–gene interactions of the Wnt/β-catenin signaling pathway in knee osteoarthritis

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...     

Regulation of cadherin expression in the chicken neural crest by the Wnt/β-catenin signaling pathway

In neural crest cell development, the expression of the cell adhesion proteins cadherin-7 and cadherin-11 commences after delamination of the neural crest cells from the neuroepithelium. The canonical Wnt signaling pathway is known to drive this delamination step and is a candidate for inducing expression of these cadherins at this time. This project was initiated to investigate the role of canonical Wnt signaling in the expression of cadherin-7 and cadherin-11 by treating neural crest cells with Wnt3a ligand. Expression of cadherin-11 was first confirmed in the neural crest cells for the chicken embryo. The changes in the expression level of cadherin-7 and -11 following the treatment with Wnt3a were studied using real-time RT-PCR and immunostaining. Statistically significant upregulation in the mRNA expression of cadherin-7 and cadherin-11 and in the amount of cadherin-7 and cadherin-11 protein found in cell-cell interfaces between neural crest cells was observed in response to Wnt, demonstrating that cadherin-7 and cadherin-11 expressed by the migrating neural crest cells can be regulated by the canonical Wnt pathway.Key words: neural crest, Wnt, cadherin-7, cadherin-11     

Wnt4 activates the canonical β-catenin pathway and regulates negatively myostatin: functional implication in myogenesis

Expression of Wnt proteins is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Previous studies have shown that Wn4 was involved in the myogenic fate of somites, in the myogenic proliferation, and differentiation of skeletal muscle. However, the function of this factor in adult muscle homeostasis remains not well understood. Here, we focus on the roles of Wnt4 during C2C12 myoblasts and satellite cells differentiation. We analyzed its myogenic activity, its mechanism of action, and its interaction with the anti-myogenic factor myostatin during differentiation. Established expression profiles indicate clearly that both types of cells express a few Wnts, and among these, only Wnt4 was not or barely detected during proliferation and was strongly induced during differentiation. As attested by myogenic factors expression pattern analysis and fusion index determination, overexpression of Wnt4 protein caused a strong increase in satellite cells and C2C12 myoblast differentiation leading to hypertrophic myotubes. By contrast, exposure of satellite and C2C12 cells to small interfering RNA against Wnt4 strongly diminished this process, confirming the myogenic activity of Wnt4. Moreover, we reported that Wnt4, which is usually described as a noncanonical Wnt, activates the canonical β-catenin pathway during myogenic differentiation in both cell types and that this factor regulates negatively the expression of myostatin and the regulating pathways associated with myostatin. Interestingly, we found that recombinant myostatin was sufficient to antagonize the differentiation-promoting activities of Wnt4. Reciprocally, we also found that the genetic deletion of myostatin renders the satellite cells refractory to the hypertrophic effect of Wnt4. These results suggest that the Wnt4-induced decrease of myostatin plays a functional role during hypertrophy. We propose that Wnt4 protein may be a key factor that regulates the extent of differentiation in satellite and C2C12 cells.     

A zebrafish Notum homolog specifically blocks the Wnt/β-catenin signaling pathway

Multiple developmental processes require tightly controlled Wnt signaling, and its misregulation leads to congenital abnormalities and diseases. Glypicans are extracellular proteins that modulate the Wnt pathway. In addition to interacting with Wnts, these glycosophosphotidylinositol (GPI)-anchored, heparan-sulfate proteoglycans bind ligands of several other signaling pathways in both vertebrates and invertebrates. In Drosophila, Notum, a secreted α/β-hydrolase, antagonizes the signaling of the prototypical Wnt Wingless (Wg), by releasing glypicans from the cell surface. Studies of mammalian Notum indicate promiscuous target specificity in cell culture, but the role of Notum in vertebrate development has not been studied. Our work shows that zebrafish Notum 1a, an ortholog of mammalian Notum, contributes to a self-regulatory loop that restricts Wnt/β-catenin signaling. Notum 1a does not interact with Glypican 4, an essential component of the Wnt/planar cell polarity (PCP) pathway. Our results suggest a surprising specific role of Notum in the developing vertebrate embryo.     

Wnk kinases are positive regulators of canonical Wnt/β-catenin signalling

Wnt/β-catenin signalling is central to development and its regulation is essential in preventing cancer. Using phosphorylation of Dishevelled as readout of pathway activation, we identified Drosophila Wnk kinase as a new regulator of canonical Wnt/β-catenin signalling. WNK kinases are known for regulating ion co-transporters associated with hypertension disorders. We demonstrate that wnk loss-of-function phenotypes resemble canonical Wnt pathway mutants, while Wnk overexpression causes gain-of-function canonical Wnt-signalling phenotypes. Importantly, knockdown of human WNK1 and WNK2 also results in decreased Wnt signalling in mammalian cell culture, suggesting that Wnk kinases have a conserved function in ensuring peak levels of canonical Wnt signalling.