Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice

Am J Respir Crit Care Med. 2009 Aug 15;180(4):326-38. doi: 10.1164/rccm.200812-1827OC. Epub 2009 Jun 4.

Abstract

Rationale: Transcriptional coactivator with PDZ-binding motif (TAZ) is assumed to act as a coactivator of several transcription factors including smad2/3. In the lung, surfactant protein C (Sftpc) is known to be a downstream target of thyroid transcription factor-1 (TTF-1)-TAZ transcriptional coactivation.

Objectives: The lung phenotype of Taz-deficient mice was explored.

Methods: Taz-deficient mice were analyzed pathologically and physiologically. Next, we performed microarray analysis to determine the genes closely related to abnormal lung development. Finally, Taz-heterozygous mice were injected with bleomycin.

Measurements and main results: Taz-deficient homozygotes showed abnormal alveolarization during lung development, which caused in adult mice airspace enlargement mimicking emphysema. There was no significant difference in the expression of Sftpc between wild-type and Taz-deficient lungs. Instead, microarray analysis identified some candidate downstream genes related to the pathogenesis, including the connective tissue growth factor (Ctgf) gene, which is required for normal lung development. In vitro studies showed that TAZ up-regulated Ctgf expression not only by reinforcing transforming growth factor-beta/smad signals, but also by interfering in the more proximal Ctgf promoter region (from bp -123 to -76), defined as the TAZ response element. Furthermore, Taz-heterozygous mice were resistant to bleomycin-induced lung fibrosis.

Conclusions: The results indicate the importance of TAZ in lung alveolarization and its involvement in the pathogenesis of lung fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin
  • Cell Differentiation / genetics*
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation / genetics
  • Homozygote
  • Intercellular Signaling Peptides and Proteins
  • Kidney / drug effects
  • Kidney / pathology
  • Lung / drug effects
  • Lung / pathology
  • Lung Compliance / drug effects
  • Lung Compliance / genetics
  • Mice
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Peptides / genetics*
  • Phenotype
  • Pulmonary Alveoli / cytology*
  • Pulmonary Alveoli / pathology
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / pathology
  • Pulmonary Surfactant-Associated Protein C
  • Reference Values
  • Smad2 Protein / genetics*
  • Smad3 Protein / genetics*
  • Transcription Factors / genetics*
  • Transcriptional Activation / genetics*
  • Up-Regulation / genetics

Substances

  • DNA-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Pulmonary Surfactant-Associated Protein C
  • Sftpc protein, mouse
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Taz protein, mouse
  • Transcription Factors
  • Ttf1 protein, mouse
  • Bleomycin