First Author | Dai H | Year | 2022 |
Journal | Front Cell Dev Biol | Volume | 10 |
Pages | 880206 | PubMed ID | 35676931 |
Mgi Jnum | J:325442 | Mgi Id | MGI:7285134 |
Doi | 10.3389/fcell.2022.880206 | Citation | Dai H, et al. (2022) Activation of PI3K/p110alpha in the Lung Mesenchyme Affects Branching Morphogenesis and Club Cell Differentiation. Front Cell Dev Biol 10:880206 |
abstractText | Epithelial-mesenchymal interaction is required for normal growth, morphogenetic patterning, and cellular differentiation in developing lungs. Various signaling pathways have been defined in establishing the patterning of this branched organ. The phosphoinositide-3-kinase (PI3K) signaling plays an important role in disease pathogenesis but remains largely uncharacterized in embryonic development. In this study, we activated a specific catalytic subunit of PI3K catalytic enzymes, Class IA p110alpha (p110alpha), in the embryonic lung mesenchyme using the Dermo1-Cre mouse. Activation of p110alpha promoted branching morphogenesis and blocked club cell differentiation in both proximal and distal airways. Mechanistically, the LIM homeodomain gene Islet-1 (Isl1), fibroblast growth factor 10 (Fgf10), and SRY (sex-determining region Y)-box9 (Sox9) were found to be downstream targets of p110alpha. The significantly increased expressions of Isl1, Fgf10, and Sox9 resulted in the stimulation of branching in mutant lungs. Activation of p110alpha-mediated signaling also increased the expression of phosphatase and tensin homolog deleted on chromosome 10 (Pten) and hairy/enhancer of split 1 (Hes1), which in turn blocked club cell differentiation. Thus, the signaling pathway by which PI3K/p110alpha-regulated epithelial-mesenchymal interactions may entail Isl1-Fgf10-Sox9 and Pten-Hes1 networks, which consequently regulate branching morphogenesis and club cell differentiation, respectively. |