Wnt signalling in lung development and diseases (original) (raw)
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Canonical Wnt Signaling Activity in Early Stages of Chick Lung Development
PLoS ONE, 2014
Wnt signaling pathway is an essential player during vertebrate embryonic development which has been associated with several developmental processes such as gastrulation, body axis formation and morphogenesis of numerous organs, namely the lung. Wnt proteins act through specific transmembrane receptors, which activate intracellular pathways that regulate cellular processes such as cell proliferation, differentiation and death. Morphogenesis of the fetal lung depends on epithelial-mesenchymal interactions that are governed by several growth and transcription factors that regulate cell proliferation, fate, migration and differentiation. This process is controlled by different signaling pathways such as FGF, Shh and Wnt among others. Wnt signaling is recognized as a key molecular player in mammalian pulmonary development but little is known about its function in avian lung development. The present work characterizes, for the first time, the expression pattern of several Wnt signaling members, such as wnt-1, wnt-2b, wnt-3a, wnt-5a, wnt-7b, wnt-8b, wnt-9a, lrp5, lrp6, sfrp1, dkk1, b-catenin and axin2 at early stages of chick lung development. In general, their expression is similar to their mammalian counterparts. By assessing protein expression levels of active/ total b-catenin and phospho-LRP6/LRP6 it is revealed that canonical Wnt signaling is active in this embryonic tissue. In vitro inhibition studies were performed in order to evaluate the function of Wnt signaling pathway in lung branching. Lung explants treated with canonical Wnt signaling inhibitors (FH535 and PK115-584) presented an impairment of secondary branch formation after 48 h of culture along with a decrease in axin2 expression levels. Branching analysis confirmed this inhibition. Wnt-FGF crosstalk assessment revealed that this interaction is preserved in the chick lung. This study demonstrates that Wnt signaling is crucial for precise chick
Gene Expression Patterns, 2010
shh Epithelium Mesenchyme a b s t r a c t Although Wnt and Hedgehog (Hh) signaling pathways play important roles in mouse lung development, these have not been explored in the development of Xenopus lung. This may be due to the lack of specific molecular markers for different layers of tissue in Xenopus lung and/or insufficient knowledge on expression patterns of Wnt and Hh signaling components in Xenopus lung. In this study, we first described the early morphogenesis of Xenopus laevis lung by using surfactant protein C (sftpc) as a marker of lung epithelium and compared it with the expression patterns of several genes of Wnt and Hh pathways in Xenopus lungs. Our data showed that wnt7b was expressed in the entire lung epithelium from stage 37 to stage 45, while two other Wnt signaling components, wnt5a and wif1 (wnt inhibitory factor 1), were expressed in the mesenchyme layer of the entire lungs through stages 39-41. We also found that sonic hedgehog (shh) was expressed at stage 41 only in the anterior, but not in the posterior part of the lungs. These results show the expression of wnt5a, wnt7b, wif1 and shh in different layers of tissue of Xenopus lungs at early developmental stages, which implies different roles of these genes in the early development of Xenopus lungs. Our study for the first time defined specific molecular markers for description of early lung development in Xenopus, as well as provided information about expression of components of Wnt and Hh pathways in early Xenopus lungs, which should be useful for future functional studies.
Hmga2is required for canonical WNT signaling during lung development
BMC Biology, 2014
Background: The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here we deciphered the role of the high-mobility-group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2-deficient mice (Hmga2 −/−). Results: We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2 −/− mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA-binding protein 6 and frizzled homolog 2. Analysis of siRNA-mediated loss-of-function experiments in embryonic lung explant culture confirmed the role of Hmga2 as a key regulator of distal lung epithelium differentiation and supported the causal involvement of enhanced canonical WNT signaling in mediating the effect of Hmga2-loss-of-fuction. Finally, we found that HMGA2 directly regulates Gata6 and thereby modulates Fzd2 expression. Conclusions: Our results support that Hmga2 regulates canonical WNT signaling at different points of the pathway. Increased expression of the secreted WNT glycoproteins might explain a paracrine effect by which Hmga2-knockout enhanced cell proliferation in the mesenchyme of the developing lung. In addition, HMGA2-mediated direct regulation of Gata6 is crucial for fine-tuning the activity of WNT signaling in the airway epithelium. Our results are the starting point for future studies investigating the relevance of Hmga2-mediated regulation of WNT signaling in the adult lung within the context of proper balance between differentiation and self-renewal of lung stem/ progenitor cells during lung regeneration in both homeostatic turnover and repair after injury.
PLOS One, 2010
The canonical Wnt/b-catenin pathway plays crucial roles in various aspects of lung morphogenesis and regeneration/repair. Here, we examined the lung phenotype and function in mice lacking the Wnt/b-catenin antagonist Chibby (Cby). In support of its inhibitory role in canonical Wnt signaling, expression of b-catenin target genes is elevated in the Cby 2/2 lung. Notably, Cby protein is prominently associated with the centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells, and later enriches as discrete foci at the base of motile cilia in airway ciliated cells. At birth, Cby 2/2 lungs are grossly normal but spontaneously develop alveolar airspace enlargement with reduced proliferation and abnormal differentiation of lung epithelial cells, resulting in altered pulmonary function. Consistent with the Cby expression pattern, airway ciliated cells exhibit a marked paucity of motile cilia with apparent failure of basal body docking. Moreover, we demonstrate that Cby is a direct downstream target for the master ciliogenesis transcription factor Foxj1. Collectively, our results demonstrate that Cby facilitates proper postnatal lung development and function.
Development, 2011
Bone morphogenetic protein 4 (Bmp4) is essential for lung development. To define the intracellular signaling mechanisms by which Bmp4 regulates lung development, BMP-specific Smad1 or Smad5 was selectively knocked out in fetal mouse lung epithelial cells. Abrogation of lung epithelial-specific Smad1, but not Smad5, resulted in retardation of lung branching morphogenesis and reduced sacculation, accompanied by altered distal lung epithelial cell proliferation and differentiation and, consequently, severe neonatal respiratory failure. By combining cDNA microarray with ChIP-chip analyses, Wnt inhibitory factor 1 (Wif1) was identified as a novel target gene of Smad1 in the developing mouse lung epithelial cells. Loss of Smad1 transcriptional activation of Wif1 was associated with reduced Wif1 expression and increased Wnt/-catenin signaling activity in lung epithelia, resulting in specific fetal lung abnormalities. This suggests a novel regulatory loop of Bmp4-Smad1-Wif1-Wnt/-catenin in coordinating BMP and Wnt pathways to control fetal lung development.
Integrating regulatory mechanisms of Wnt signaling in development and tissue homeostasis
2017
Evolutionarily conserved signal transduction pathways mediate the ability of cells to respond to their environment and coordinate with each other for proper development and homeostasis of an organism. The Wnt/Wingless (Wg) pathway is required for proliferation, differentiation, stem-cell renewal and homeostasis, and when disrupted leads to disease. Wnt signaling does not control all these processes alone, its activity is extensively regulated by interaction with other signaling pathways and cellular mechanisms. This is mediated predominantly through phospho-regulation of the key pathway components by kinases and phosphatases. Our lab conducted an in vivo RNAi screen designed to identify novel kinase and phosphatase regulators of the Wnt pathway. In my PhD thesis research I further characterized three potential regulators: Downstream of Raf1 (Dsor1), Protein phosphatase 4 (PP4), and myosin phosphatase. Knockdown of Dsor1 reduced Wnt target gene expression and decreased stabilized βcatenin, the key effector protein of the Wnt pathway. Dsor1 and β-catenin had a close physical interaction, and catalytically inactive Dsor1 caused a reduction in active βcatenin, suggesting that Dsor1 counteracts destruction of β-catenin. Additionally, Ras-Dsor1 activity was independent of EGFR, and likely activated by the insulin-like receptor to promote Wnt. This work demonstrates novel crosstalk between Insulin and Wnt signaling via Dsor1. The reduction of PP4 inhibited Wg pathway activity, by reducing Notch-driven wg transcription. PP4 was found to promote Notch signaling within the nucleus of the receiving cell. Furthermore, PP4 regulates proliferation independently of its Notch interaction. This study identified a new role for PP4 in Notch signaling, and subsequently transcriptional regulation of wg. Reduced myosin phosphatase inhibited Wnt signaling by causing increased non-muscle myosin II (NMII) activation and cellular contraction. NMII activation stabilizes cortical F-actin resulting in accumulation of Ecadherin to the adherens junctions (AJ). E-cadherin titrates available β-catenin to the AJs in order to maintain cell-cell adhesion under contraction. The decreased cytoplasmic β-catenin results in insufficient nuclear translocation for full Wnt target gene transcription. This work elucidates that the dynamic activation of actomyosin contractility refines patterning of Wnt target gene expression. These studies identified three novel regulatory mechanisms for controlling Wnt signaling in development and homeostasis.
Scientific Reports, 2020
Lung malignancies comprise lethal and aggressive tumours that remain the leading cancer-related death cause worldwide. Regarding histological classification, lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) account for the majority of cases. Surgical resection and various combinations of chemo- and radiation therapies are the golden standards in the treatment of lung cancers, although the five-year survival rate remains very poor. Notch, Hedgehog, Wnt and Erbb signalling are evolutionarily conserved pathways regulating pivotal cellular processes such as differentiation, proliferation, and angiogenesis during embryogenesis and post-natal life. However, to date, there is no study comprehensively revealing signalling networks of these four pathways in LUSC and LUAD. Therefore, the aim of the present study was the investigation profiles of downstream target genes of pathways that differ between LUSC and LUAD biology. Our results showed a few co-expression modules, identifie...
A Role for Wnt Signaling Genes in the Pathogenesis of Impaired Lung Function in Asthma
American Journal of Respiratory and Critical Care Medicine, 2010
At-a-Glance Commentary: Scientific Knowledge on the Subject: The trajectory of lung function growth appears to be set early in life. Animal models demonstrate that abnormal in utero expression of genes implicated in normal lung development can result in abnormal pulmonary phenotypes after birth.