Lung mesenchymal expression of Sox9 plays a critical role in tracheal development
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RESEARCH ARTICLE
Open Access
Lung mesenchymal expression of Sox9 plays a critical role in tracheal development Gianluca Turcatel1, Nicole Rubin1, Douglas B Menke2, Gary Martin3, Wei Shi1 and David Warburton1*
Abstract Background: 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. Sox9 is expressed in both distal lung epithelium and proximal lung mesenchyme. Here, we investigated the effect of lung mesenchymespecific inducible deletion of Sox9 during murine lung development. Results: Transgenic 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. Conclusion: The 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. Keywords: Sox9, Trachea, Lung, Cartilage, CC10, P63
Background The development of the respiratory system represents an evolutionary hallmark that allowed vertebrates to survive on land utilizing air as a source of oxygen. Abnormal development of the respiratory system in humans is associated with multiple disorders such as tracheal/bronchial atresia, tracheo-esophageal fistula, bronchogenic cysts, pulmonary/lobar atresia, and pulmonary hypoplasia [1]. In the embryonic trachea, 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 * Correspondence: [email protected] 1 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children’s Hospital Los Angeles, Keck School of Medicine and Ostrow School of Dentistry, University of Southern California, 4661 Sunset Boulevard, Los Angeles, CA 90027, USA Full list of author information is available at the end of the article
to create C-shaped cartilage ring
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