β‐catenin and Kras/Foxm1 signaling pathway are critical to restrict Sox9 in basal cells during pulmonary branching morphogenesis

Abstract

Background Lung morphogenesis is regulated by interactions between the canonical Wnt/β-catenin and Kras/ERK/Foxm1 signaling pathways that establish proximal-peripheral patterning of lung tubules. How these interactions influence the development of respiratory epithelial progenitors to acquire airway as compared to alveolar epithelial cell fate is unknown. During branching morphogenesis, SOX9 transcription factor is normally restricted from conducting airway epithelial cells and is highly expressed in peripheral, acinar progenitor cells that serve as precursors of alveolar type 2 (AT2) and AT1 cells as the lung matures. Results To identify signaling pathways that determine proximal-peripheral cell fate decisions, we used the SFTPC gene promoter to delete or overexpress key members of Wnt/β-catenin and Kras/ERK/Foxm1 pathways in fetal respiratory epithelial progenitor cells. Activation of β-catenin enhanced SOX9 expression in peripheral epithelial progenitors, whereas deletion of β-catenin inhibited SOX9. Surprisingly, deletion of β-catenin caused accumulation of atypical SOX9-positive basal cells in conducting airways. Inhibition of Wnt/β-catenin signaling by KrasG12D or its downstream target Foxm1 stimulated SOX9 expression in basal cells. Genetic inactivation of Foxm1 from KrasG12D-expressing epithelial cells prevented the accumulation of SOX9-positive basal cells in developing airways. Conclusions Interactions between the Wnt/β-catenin and the Kras/ERK/Foxm1 pathways are essential to restrict SOX9 expression in basal cells.

Temporal, spatial, and phenotypical changes of PDGFRα expressing fibroblasts during late lung development

“…HOPX can be found in the cytoplasm and nucleus. SOX9 is restricted to distal acinar buds and is essential for early branching morphogenesis, distal epithelial differentiation, and extracellular matrix organization (Perl et al, 2005; Rockich et al, 2013; Ustiyan et al, 2016). The SOX9 protein is localized to the nucleus and is also rarely expressed in some fibroblasts adjacent to the mature peribronchiolar smooth muscle layer.…”

Pre- and postnatal exposure of mice to concentrated urban PM2.5 decreases the number of alveoli and leads to altered lung function at an early stage of life

“…At E14.5, it is expressed in the epithelial buds of distal airways (Eurexpress atlas) (Diez-Roux et al, 2011). Information about its role during lung development remain highly scarce compared to the better studied role of the related SoxE group member Sox9 which has been shown to be a regulator in branching lung morphogenesis and differentiation of respiratory epithelial progenitors (Chang et al, 2013; Rockich et al, 2013; Ustiyan et al, 2016), being linked to Wnt/β-catenin as well as Kras signaling (Caprioli et al, 2015; Rockich et al, 2013; Ustiyan et al, 2016). Sox8-deficient mice exhibit reduced body weight starting at postnatal week 3 (Sock et al, 2001).…”

β-Catenin maintains lung epithelial progenitors after lung specification

“…To test whether CTNNB1 activation was sufficient to promote SOX9 progenitors, we activated a stabilized version of CTNNB1 in E11 SOX9 progenitors, which would contribute to most of the lung epithelium by E15 (Rawlins et al, 2009;Alanis et al, 2014). Different from previous mouse models using Spc drivers that were possibly active before E11 (Hashimoto et al, 2012;Ustiyan et al, 2016), we did not observe any changes in branch morphology or expression of SOX9 and SOX2, even though the cartilage rings, which were also targeted by Sox9 CreER , were defective in the same mutant lung, and stabilization of CTNNB1 before lung specification using Shh Cre completely blocked branching (Fig. S5).…”