Formation and Differentiation of Multiple Mesenchymal Lineages during Lung Development Is Regulated by β-catenin Signaling

Langhe, Stijn P. De; Carraro, Gianni; Tefft, Denise; Li, Changgong; Xu, Xin; Chai, Yang; Minoo, Parviz; Hajihosseini, Mohammad K.; Drouin, Jacques; Kaartinen, Vesa; Bellusci, Savério

doi:10.1371/journal.pone.0001516

Cited by 110 publications

(155 citation statements)

References 50 publications

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…␤-Catenin signaling is essential for cell fate determination in epithelium and mesenchyme in the developing lung (38,39). In the absence of Wnt signal, ␤-catenin is phosphorylated at several serine-threonine sites by glycogen synthase kinase 3␤ and casein kinase and is subsequently marked for proteasomal degradation (36,40,41).…”

Section: Discussionmentioning

confidence: 99%

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Weng¹,

Gao

Bhaskaran

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The role of pleiotrophin in fetal lung development was investigated. We found that pleiotrophin and its receptor, proteintyrosine phosphatase receptor ␤/, were highly expressed in mesenchymal and epithelial cells of the fetal lungs, respectively. Using isolated fetal alveolar epithelial type II cells, we demonstrated that pleiotrophin promoted fetal type II cell proliferation and arrested type II cell trans-differentiation into alveolar epithelial type I cells. Pleiotrophin also increased wound healing of injured type II cell monolayer. Knockdown of pleiotrophin influenced lung branching morphogenesis in a fetal lung organ culture model. Pleiotrophin increased the tyrosine phosphorylation of ␤-catenin, promoted ␤-catenin translocation into the nucleus, and activated T cell factor/lymphoid enhancer factor transcription factors. Dlk1, a membrane ligand that initiates the Notch signaling pathway, was identified as a downstream target of the pleiotrophin/␤-catenin pathway by endogenous dlk1 expression, promoter assay, and chromatin immunoprecipitation. These results provide evidence that pleiotrophin regulates fetal type II cell proliferation and differentiation via integration of multiple signaling pathways including pleiotrophin, ␤-catenin, and Notch pathways.Fetal lung development is a complex biological process. Rat lung originates from the foregut endoderm as a bifurcation at embryonic day 10 (E10) and undergoes several generations of dichotomous branching morphogenesis to form a respiratory tree thereafter (1). The columnar epithelial cells differentiate into Clara cells and epithelial cells. Although surfactant protein C is detected as early as E13, fetal alveolar epithelial type II cells (fAEC II) 3 are not fully differentiated until E18 when glycogen pool-enriched cells become cuboidal and differentiate into cells containing lamellar bodies. fAEC II can further differentiate and give rise to the alveolar epithelial type I cells (AEC I).The regulation of fetal lung development includes coordinated regulation of molecular pathways as well as reciprocal interactions among mesenchymal cells, epithelial cells, and the extracellular matrix (2). Precise signals from mesenchymal cells regulate lung branching morphogenesis and lead to cell fate determination and the subsequent generation of cell type diversity in the lung epithelium. For example, mesenchymal cells secrete fibroblast growth factor 10 (3, 4). Fibroblast growth factor 10 in turn binds to its receptor, which is located on the surface of epithelial cells. The binding transduces a message to downstream signaling to regulate cell proliferation, differentiation, migration, and branching morphogenesis. Similarly, the epithelial cells also secrete signal molecules to interact with the mesenchyme. Sonic hedgehog (Shh) is growth factor expressed in the developing epithelium. Its receptor, Patched-1 (Ptc), is located on mesenchymal cells. The interaction between Shh and Ptc has been shown to be required for lung bud formation (5). Other growth factors such as pl...

show abstract

Section: Discussionmentioning

confidence: 99%

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Weng¹,

Gao

Bhaskaran

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…On the one hand, Wnt7b/β-catenin signaling is an important factor for ASM development, 80 and on the other hand, β-catenin induces proliferation of ASM. 81,82 Moreover, not only proliferation but also contraction of ASM is affected by Wnt/β-catenin signaling. In ASM, β-catenin exists as membrane-associated protein in a complex with actin filament facilitating cell-cell contacts.…”

Section: Role Of Wnt Pathways In Airway Remodelingmentioning

confidence: 99%

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Reuter

Beckert

Taube

2016

Laboratory Investigation

View full text Add to dashboard Cite

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases that are associated with inflammation and structural changes in the airways and lungs. Recent findings have implicated Wnt pathways in critically regulating inflammatory responses, especially in asthma. Furthermore, canonical and noncanonical Wnt pathways are involved in structural changes such as airway remodeling, goblet cell metaplasia, and airway smooth muscle (ASM) proliferation. In COPD, Wnt pathways are not only associated with structural changes in the airways but also involved in the development of emphysema. The present review summarizes the role and function of the canonical and noncanonical Wnt pathway with regard to airway inflammation and structural changes in asthma and COPD. Further identification of the role and function of different Wnt molecules and pathways could help to develop novel therapeutic options for these diseases.

show abstract

“…1D,E). Gpr177 was also deleted in the mesenchyme with Dermo1-Cre (Derm1-Cre), which is activated at ~E10.5 (De Langhe et al, 2008), and the mutants die between E15.5 and 17.5 without hemorrhage or visible vasculature defects (supplementary material Fig. S1I,J).…”

Section: ∆/∆mentioning

confidence: 99%

Gpr177 regulates pulmonary vasculature development

Jiang

et al. 2013

Development

View full text Add to dashboard Cite

Establishment of the functional pulmonary vasculature requires intimate interaction between the epithelium and mesenchyme. Previous genetic studies have led to inconsistent conclusions about the contribution of epithelial Wnts to pulmonary vasculature development. This discrepancy is possibly due to the functional redundancy among different Wnts. Here, we use Shh-Cre to conditionally delete Gpr177 (the mouse ortholog of Drosophila Wntless, Wls), a chaperon protein important for the sorting and secretion of Wnt proteins. Deletion of epithelial Gpr177 reduces Wnt signaling activity in both the epithelium and mesenchyme, resulting in severe hemorrhage and abnormal vasculature, accompanied by branching defects and abnormal epithelial differentiation. We then used multiple mouse models to demonstrate that Wnt/β-catenin signaling is not only required for the proliferation and differentiation of mesenchyme, but also is important for the maintenance of smooth muscle cells through the regulation of the transcription factor Kruppel-like factor 2 (Klf2). Together, our studies define a novel mechanism by which epithelial Wnts regulate the normal development and maintenance of pulmonary vasculature. These findings provide insight into the pathobiology of congenital lung diseases, such as alveolar capillary dysplasia (ACD), that have abnormal alveolar development and dysmorphic pulmonary vasculature.

show abstract

Formation and Differentiation of Multiple Mesenchymal Lineages during Lung Development Is Regulated by β-catenin Signaling

Cited by 110 publications

References 50 publications

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Gpr177 regulates pulmonary vasculature development

Contact Info

Product

Resources

About