Abstract
BackgroundEmbryonic lung development is instructed by crosstalk between mesenchyme and epithelia, which results in activation of transcriptional factors, such as Sox9, in a temporospatial manner. Sox9 is expressed in both distal lung epithelium and proximal lung mesenchyme. Here, we investigated the effect of lung mesenchyme-specific inducible deletion of Sox9 during murine lung development.ResultsTransgenic mice lacking Sox9 expression were unable to breathe and died at birth, with noticeable tracheal defects. Cartilage rings were missing, and the tracheal lumen was collapsed in the mutant trachea. In situ hybridization showed an altered expression pattern of Tbx4, Tbx5 and Fgf10 genes and marked reduction of Collagen2 expression in the tracheal mesenchyme. The tracheal phenotype was increasingly severe, with longer duration of deletion. Lymphatic vasculature was underdeveloped in the mutant trachea: Prox1, Lyve1, and Vegfr3 were decreased after Sox9 knockout. We also found that compared with normal tracheal epithelium, the mutant tracheal epithelium had an altered morphology with fewer P63-positive cells and more CC10-positive cells, fewer goblet cells, and downregulation of surfactant proteins A and C.ConclusionThe appropriate temporospatial expression of Sox9 in lung mesenchyme is necessary for appropriate tracheal cartilage formation, lymphatic vasculature system development, and epithelial differentiation. We uncovered a novel mechanism of lung epithelium differentiation: tracheal cartilage rings instruct the tracheal epithelium to differentiate properly during embryonic development. Thus, besides having a mechanical function, tracheal cartilage also appears to be a local signaling structure in the embryonic lung.
Highlights
Embryonic lung development is instructed by crosstalk between mesenchyme and epithelia, which results in activation of transcriptional factors, such as Sox9, in a temporospatial manner
At E15.5, mesenchymal cells expressing Sox9 cells are condensed at the area of the future cartilage rings, while epithelial cells expressing Sox9 are localized in the distal lung epithelium (Figure 1B)
We have identified an important mechanism by which mesenchymal Sox9expressing cells instruct tracheal cartilage, epithelial, and lymphatic differentiation in a phenotype that already appears to model and may perhaps explain mechanistically some extreme cases of primary tracheomalacia in human new born infants
Summary
Embryonic lung development is instructed by crosstalk between mesenchyme and epithelia, which results in activation of transcriptional factors, such as Sox, in a temporospatial manner. The endoderm differentiates into a ciliated pseudo-stratified epithelium, which includes basal P63+ cells, Clara cells, neuroendocrine cells, and ciliated cells. The ventral mesenchyme gradually matures β-catenin, Bmp, and Shh are previously well-characterized regulators of cartilage formation, which may activate the Sox gene in mesenchymal cells to induce their differentiation into chondrocytes. Members of the fibroblast growth factor superfamily, including Fgf, Fgf, and Fgf, are key regulators of cartilage formation [4,5]. Tbx and Tbx double knockout in lung resulted in defects of cartilage formation in mouse trachea and in altered lung branching, with Tbx and Tbx acting upstream of Sox in tracheal cartilage development [7]
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