-Catenin-SOX2 signaling regulates the fate of developing airway epithelium

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, 106 Research Drive, 2075 MSRBII, DUMC Box 103000, Durham, NC, 27710, USA.
Journal of Cell Science (Impact Factor: 5.43). 03/2012; 125(Pt 4):932-42. DOI: 10.1242/jcs.092734
Source: PubMed


Wnt-β-catenin signaling regulates cell fate during organ development and postnatal tissue maintenance, but its contribution to specification of distinct lung epithelial lineages is still unclear. To address this question, we used a Cre recombinase (Cre)-LoxP approach to activate canonical Wnt signaling ectopically in developing lung endoderm. We found that persistent activation of canonical Wnt signaling within distal lung endoderm was permissive for normal development of alveolar epithelium, yet led to the loss of developing bronchiolar epithelium and ectasis of distal conducting airways. Activation of canonical Wnt led to ectopic expression of a lymphoid-enhancing factor and a T-cell factor (LEF and TCF, respectively) and absence of SRY (sex-determining region Y)-box 2 (SOX2) and tumor protein p63 (p63) expression in proximal derivatives. Conditional loss of SOX2 in airways phenocopied epithelial differentiation defects observed with ectopic activation of canonical Wnt. Our data suggest that Wnt negatively regulates a SOX2-dependent signaling program required for developmental progression of the bronchiolar lineage.

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    • "The molecular phenotypes of developing proximal and distal lung epithelial cell lineages have been associated with the differential expression of the transcription factors Sox2 and Sox9—sex-determining region Y (SRY)-box 2 and 9 [31]. Sox genes are highly conserved throughout the animal kingdom [32] and Sox2 has been implicated as an early marker for proximal lung cell differentiation [33] whereas Sox9 has been increasingly connected with distal respiratory trajectories [34]. "
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    ABSTRACT: Background Claudins are transmembrane proteins expressed in tight junctions that prevent paracellular transport of extracellular fluid and a variety of other substances. However, the expression profile of Claudin-6 (Cldn6) in the developing lung has not been characterized. Methods and results Cldn6 expression was determined during important periods of lung organogenesis by microarray analysis, qPCR and immunofluorescence. Expression patterns were confirmed to peak at E12.5 and diminish as lung development progressed. Immunofluorescence revealed that Cldn6 was detected in cells that also express TTF-1 and FoxA2, two critical transcriptional regulators of pulmonary branching morphogenesis. Cldn6 was also observed in cells that express Sox2 and Sox9, factors that influence cell differentiation in the proximal and distal lung, respectively. In order to assess transcriptional control of Cldn6, 0.5, 1.0, and 2.0-kb of the proximal murine Cldn6 promoter was ligated into a luciferase reporter and co-transfected with expression vectors for TTF-1 or two of its important transcriptional co-regulators, FoxA2 and Gata-6. In almost every instance, TTF-1, FoxA2, and Gata-6 activated gene transcription in cell lines characteristic of proximal airway epithelium (Beas2B) and distal alveolar epithelium (A-549). Conclusions These data revealed for the first time that Cldn6 might be an important tight junctional component expressed by pulmonary epithelium during lung organogenesis. Furthermore, Cldn6-mediated aspects of cell differentiation may describe mechanisms of lung perturbation coincident with impaired cell junctions and abnormal membrane permeability.
    Respiratory Research 06/2014; 15(1):70. DOI:10.1186/1465-9921-15-70 · 3.09 Impact Factor
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    • "Both signalling systems may be associated with the higher structural plasticity that is characteristic for the terminal airways [37]. Wnt-signalling has recently been associated with fate decisions in the developing mammalian lung [38]. Additional differences are obvious in the stress response genes specifically expressed in either of both areas indicating differential susceptibility to stressors. "
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    ABSTRACT: Although airway epithelia are primarily devoted to gas exchange, they have to fulfil a number of different tasks including organ maintenance and the epithelial immune response to fight airborne pathogens. These different tasks are at least partially accomplished by specialized cell types in the epithelium. In addition, a proximal to distal gradient mirroring the transition from airflow conduction to real gas exchange, is also operative. We analysed the airway system of larval Drosophila melanogaster with respect to region-specific expression in the proximal to distal axis. The larval airway system is made of epithelial cells only. We found differential expression between major trunks of the airways and more distal ones comprising primary, secondary and terminal ones. A more detailed analysis was performed using DNA-microarray analysis to identify cohorts of genes that are either predominantly expressed in the dorsal trunks or in the primary/secondary/terminal branches of the airways. Among these differentially expressed genes are especially those involved in signal transduction. Wnt-signalling associated genes for example are predominantly found in secondary/terminal airways. In addition, some G-protein coupled receptors are differentially expressed between both regions of the airways, exemplified by those activated by octopamine or tyramine, the invertebrate counterparts of epinephrine and norepinephrine. Whereas the OAMB is predominantly found in terminal airway regions, the oct3ßR has higher expression levels in dorsal trunks. In addition, we observed a significant association of both, genes predominantly expressed in dorsal trunks or in primary to terminal branches branches with those regulated by hypoxia. Taken together, this observed differential expression is indicative for a proximal to distal transcriptional regionalization presumably reflecting functional differences in these parts of the fly’s airway system.
    PLoS ONE 06/2014; 9(7). DOI:10.1371/journal.pone.0102534 · 3.23 Impact Factor
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    ABSTRACT: Human airways are a paragon of intrinsic engineering. They experience 7,000-10,000 liters of airflow/day, have a 70-m(2) surface area, and undergo complete renewal every 100-400 days. Despite this, airways are susceptible to aging, injury, and diseases that are major causes of mortality. Current airway regeneration research is focused both on understanding the cells and strategies responsible for maintaining intrinsic tissue homeostasis as well as on establishing clinical interventions for improving repair.
    Physiology 06/2012; 27(3):140-7. DOI:10.1152/physiol.00001.2012 · 4.86 Impact Factor
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