title: Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mitani
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fukuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Makita
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
mesh_terms: D000217:Acyltransferases; D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006720:Homozygote; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008170:Lung Compliance / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000235:genetics / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D037721:Pulmonary Surfactant-Associated Protein C; D012016:Reference Values; D051899:Smad2 Protein / Q000235:genetics*; D051900:Smad3 Protein / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014157:Transcription Factors; C504004:Ttf1 protein, mouse; D001761:Bleomycin; D000217:Acyltransferases; C486363:tafazzin protein, mouse