Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1
Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1
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DOI：
10.1073/pnas.0605266104
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发表时间：
2007-01-30
影响因子：
11.1
通讯作者：
Hunziker, Walter
中科院分区：
文献类型：
--
作者：
Hossain, Zakir;Ali, Safiah Mohamed;Hunziker, Walter
Wwtr1是一种广泛表达的14 - 3 - 3结合蛋白，它调节参与发育和疾病的几种转录因子的活性。为了阐明Wwtr1的生理作用，我们通过同源重组产生了Wwtr1（-/-）小鼠。令人惊讶的是，尽管已知Wwtr1调节Cbfa1（一种对骨骼发育很重要的转录因子）的活性，但Wwtr1（-/-）小鼠仅表现出轻微的骨骼缺陷。然而，Wwtr1（-/-）动物出现肾囊肿，导致终末期肾病。囊肿主要源于鲍曼氏腔的扩张和肾小球丛的萎缩，类似于人类的肾小球囊性肾病。一小部分囊肿来自肾小管，特别是集合管（CID）。囊肿在皮质髓质的聚集也与肾单位肾痨有相似之处。囊肿内壁的细胞具有更少且更短的纤毛，并且几种与肾小球囊性肾病相关的基因（Ofd1和Tsc1）或编码参与纤毛结构和/或功能的蛋白质的基因（Tg737、Kif3a和Dctn5）在Wwtr1（-/-）肾脏中的表达降低。通过使用小干扰RNA降低Wwtr1蛋白水平，可以在肾集合管上皮细胞系mIIMCD3中重现纤毛完整性的丧失以及Dctn5、Kif3a、Pkhd1和Ofd1 mRNA表达的下调。因此，Wwtr1对肾纤毛的完整性至关重要，其在小鼠中的缺失导致肾囊肿的形成，这表明Wwtr1可能是人类多囊肾病的一个候选基因。
Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1(-/-) mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for bone development, Wwtr1(-/-) mice show only minor skeletal defects. However, Wwtr(1-/-) animals present with renal cysts that lead to end-stage renal disease. Cysts predominantly originate from the dilation of Bowman's spaces and atrophy of glomerular tufts, reminiscent of glomerulocystic kidney disease in humans. A smaller fraction of cysts is derived from tubules, in particular the collecting duct (CID). The corticomedullary accumulation of cysts also shows similarities with nephronophthisis. Cells lining the cysts carry fewer and shorter cilia and the expression of several genes associated with glomerulocystic kidney disease (Ofd1 and Tsc1) or encoding proteins involved in cilia structure and/or function (Tg737, Kif3a, and Dctn5) is decreased in Wwtr1(-/-) kidneys. The loss of cilia integrity and the down-regulation of Dctn5, Kif3a, Pkhd1 and Ofd1 mRNA expression can be recapitulated in a renal CD epithelial cell line, mIIMCD3, by reducing Wwtr1 protein levels using siRNA. Thus, Wwtr1 is critical for the integrity of renal cilia and its absence in mice leads to the development of renal cysts, indicating that Wwtr1 may represent a candidate gene for polycystic kidney disease in humans.