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1 Department of Physiological Chemistry and Metabolism, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan; Department of Developmental Medical Technology (Sankyo), The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
2 Department of Physiological Chemistry and Metabolism, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
3 Department of Developmental Medical Technology (Sankyo), The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
4 Department of Urology, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
5 Department of Physiological Chemistry and Metabolism, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan; Department of Respiratory Medicine, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
6 Department of Respiratory Medicine, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
7 Department of Laboratory Medicine, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
8 Genome Science Division, RCAST, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
9 Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States; Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States
10 Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States
11 Departments of Internal Medicine and Pediatrics, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States
12 Department of Physiological Chemistry and Metabolism, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan; Department of Biomedical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Japan
* To whom correspondence should be addressed. E-mail: kuri-tky{at}umin.ac.jp.
TAZ (transcriptional coactivator with PDZ-binding motif), also called WWTR1 (WW domain containing transcription regulator 1), is a 14-3-3-binding molecule homologous to Yes-associated protein (YAP). TAZ acts as a coactivator for several transcription factors as well as a modulator of membrane-associated PDZ domain-containing proteins, but its (patho)physiological roles remain unknown. Here we show that gene inactivation of TAZ in mice resulted in pathological changes in the kidney and lung that resemble the common human diseases, polycystic kidney disease and pulmonary emphysema. Taz-null/lacZ knock-in mutant homozygotes demonstrated renal cyst formation as early as embryonic day 15.5 with dilatation of Bowman's capsules and proximal tubules, followed by pelvic dilatation and hydronephrosis. After birth, only one-fifth of TAZ-deficient homozygotes grew to adulthood and demonstrated multicystic kidneys with severe urinary concentrating defects and polyuria. Furthermore, adult TAZ-deficient homozygotes exhibited diffuse emphysematous changes in the lung. Thus, TAZ is essential for developmental mechanisms involved in kidney and lung organogenesis, whose disturbance may lead to the pathogenesis of common human diseases.
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