Lung mesenchymal expression of Sox9plays a critical role in tracheal development

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.

Alterations in Gene Expression and DNA Methylation during Murine and Human Lung Alveolar Septation

“…These included genes involved with the immune system, antioxidant defense, extracellular matrix (ECM) formation, and lung cancer. Genes previously reported in other studies to be important in lung development (WNT1 inducible signaling pathway protein 2 [24],WNT inhibitory factor 1 [25], angiopoietin 2 [26], and sex-determining region Y-box 9 [27]) were also observed in our study, further validating their importance, as well as offering insight into the role DNA methylation may have in regulating their expression. A number of genes with less obvious significance to alveolar septation were also noted, and further evaluation of these targets is required to determine their role in septation.…”

Sox9 Activation is Essential for the Recovery of Lung Function after Acute Lung Injury

“…The transcription factor Sox9 has been extensively studied and highlighted its critical role during the developmental branching morphogenesis of embryonic lung [13][14][15]. Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in a developed lung [13][14][15].…”

“…Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in a developed lung [13][14][15]. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are required to ensure the proper branching morphogenesis [13][14][15].…”

“…Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in a developed lung [13][14][15]. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are required to ensure the proper branching morphogenesis [13][14][15]. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at late embryonic day, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells [13][14][15].…”

“…Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are required to ensure the proper branching morphogenesis [13][14][15]. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at late embryonic day, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells [13][14][15]. Fine regulation of Sox9 levels is needed for balancing proliferation and differentiation of epithelial tip progenitor cells [13][14][15].…”