Makita Ryosuke, Uchijima Yasunobu, Nishiyama Koichi, Amano Tomokazu, Chen Qin, Takeuchi Takumi, Mitani Akihisa, Nagase Takahide, Yatomi Yutaka, Aburatani Hiroyuki, Nakagawa Osamu, Small Erin V, Cobo-Stark Patricia, Igarashi Peter, Murakami Masao, Tominaga Junji, Sato Takahiro, Asano Tomoichiro, Kurihara Yukiko, Kurihara Hiroki
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Am J Physiol Renal Physiol. 2008 Mar;294(3):F542-53. doi: 10.1152/ajprenal.00201.2007. Epub 2008 Jan 2.
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. 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 knockin 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.
TAZ（含PDZ结合基序的转录共激活因子），也称为WWTR1（含WW结构域的转录调节因子1），是一种与Yes相关蛋白同源的14-3-3结合分子。TAZ作为几种转录因子的共激活因子以及膜相关含PDZ结构域蛋白的调节剂，但其（病理）生理作用仍不清楚。在此我们表明，小鼠中TAZ的基因失活导致肾脏和肺部出现病理变化，类似于人类常见疾病多囊肾病和肺气肿。TAZ基因敲除/ lacZ敲入突变纯合子早在胚胎第15.5天就出现肾囊肿形成，伴有鲍曼囊和近端小管扩张，随后出现肾盂扩张和肾积水。出生后，只有五分之一的TAZ缺陷纯合子存活至成年，并表现出多囊肾，伴有严重的尿液浓缩缺陷和多尿。此外，成年TAZ缺陷纯合子在肺部表现出弥漫性肺气肿变化。因此，TAZ对于肾脏和肺器官发生所涉及的发育机制至关重要，其紊乱可能导致常见人类疾病的发病机制。
