Sox2 regulates the emergence of lung basal cells by directly activating the transcription of Trp63

Am J Respir Cell Mol Biol. 2014 Aug;51(2):311-22. doi: 10.1165/rcmb.2013-0419OC.

Abstract

Lung development is determined by the coordinated expression of several key genes. Previously, we and others have shown the importance of the sex determining region Y-box 2 (Sox2) gene in lung development. Transgenic expression of Sox2 during lung development resulted in cystic airways, and here we show that modulating the timing of ectopic Sox2 expression in the branching regions of the developing lung results in variable cystic lesions resembling the spectrum of the human congenital disorder congenital cystic adenomatoid malformation (CCAM). Sox2 dominantly differentiated naive epithelial cells into the proximal lineage irrespective of the presence of Fgf10. Sox2 directly induced the expression of Trp63, the master switch toward the basal cell lineage and induced the expression of Gata6, a factor involved in the emergence of bronchoalveolar stem cells. We showed that SOX2 and TRP63 are coexpressed in the lungs of human patients with type II CCAM. The combination of premature differentiation toward the proximal cell lineage and the induction of proliferation resulted in the cyst-like structures. Thus, we show that Sox2 is directly responsible for the emergence of two lung progenitor cells: basal cells by regulating the master gene Trp63 and bronchoalveolar stem cells by regulating Gata6.

Keywords: Sox2; Trp63; basal cells; bronchoalveolar stem cell; lung.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Proliferation
  • Cystic Adenomatoid Malformation of Lung, Congenital / genetics
  • Cystic Adenomatoid Malformation of Lung, Congenital / metabolism*
  • Cystic Adenomatoid Malformation of Lung, Congenital / pathology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Fibroblast Growth Factor 10 / metabolism
  • GATA6 Transcription Factor / metabolism
  • Gene Expression Regulation, Developmental
  • Genotype
  • Gestational Age
  • HEK293 Cells
  • Humans
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • Tissue Culture Techniques
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Transcriptional Activation*
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Fgf10 protein, mouse
  • Fibroblast Growth Factor 10
  • GATA6 Transcription Factor
  • Gata6 protein, mouse
  • Phosphoproteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Trp63 protein, mouse
  • Tumor Suppressor Proteins