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Transcriptional Coactivator with PDZ-binding Motif Is Essential for Normal Alveolarization in Mice

¹ Department of Respiratory Medicine and ² Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo; ³ Bioscience Division II, Discovery Research Laboratories, Kyorin Pharmaceutical Company, Nogi, Tochigi; and ⁴ Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Takahide Nagase, M.D., Ph.D., Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: takahide-tky{at}umin.ac.jp

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-β/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.

Key Words: Taz-deficient mice • emphysema • lung development • pulmonary fibrosis • connective tissue growth factor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject TAZ (transcriptional coactivator with PDZ-binding motif) is a factor critical for lung alveolarization, and connective tissue growth factor (CTGF) may be involved in this process. In vitro studies have shown that TAZ up-regulates Ctgf expression not only by reinforcing TGF-β/smad signals, but also by interfering with the more proximal Ctgf promoter region. Furthermore, Taz-heterozygous mice are resistant to bleomycin-induced lung fibrosis. What This Study Adds to the Field This study shows that TAZ is an important factor in lung alveolarization and is involved in the pathogenesis of lung fibrosis.