title: Lung mesenchymal expression of Sox9 plays a critical role in tracheal development.
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 mesenchyme-specific 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.
  
  
  CONCLUSIONS
  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.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Turcatel
authors.forename: Nicole
authors.initials: N
authors.lastname: Rubin
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Menke
authors.forename: Gary
authors.initials: G
authors.lastname: Martin
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: 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. dwarburton@chla.usc.edu.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
mesh_terms: D000818:Animals; D002356:Cartilage / Q000196:embryology; D004318:Doxycycline; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000196:embryology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C103177:Tbx4 protein, mouse; D014157:Transcription Factors; D004318:Doxycycline