Novel zebrafish polycystic kidney disease (PKD) models reveal functions of the Hippo pathway in renal cystogenesis.,Disease Models & Mechanisms |
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Novel zebrafish polycystic kidney disease (PKD) models reveal functions of the Hippo pathway in renal cystogenesis.,Disease Models & Mechanisms
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Hippo signaling pathway is a kinase cascade which plays an important role in organ size control. As the main effectors of the Hippo pathway, transcription coactivators Yap1/Wwtr1 are regulated by the upstream kinase Stk3. Recent studies in mammals have implicated Hippo pathway in kidney development and kidney diseases. To further illustrate its roles in vertebrate kidney, we generated a series of zebrafish mutants targeting stk3, yap1 and wwtr1 genes. The stk3-/- mutant exhibited edema, formation of glomerular cysts and pronephric tubule dilation during larval stage. Interestingly, disruption of wwtr1 but not yap1 significantly alleviated the renal phenotypes of the stk3-/- mutant, and overexpression of Wwtr1 with CMV promoter also induced pronephric phenotypes during larval stage, similar to those of the stk3-/- mutant. Notably, adult fish with Wwtr1 overexpression developed phenotypes similar to those of human polycystic kidney disease (PKD). Overall, our studies revealed roles of Stk3 and Wwtr1 in renal cyst formation. Using pharmacological approach, we further demonstrated that Stk3-deficient zebrafish could serve as a PKD model for drug development.
中文翻译：
Hippo信号通路是一种激酶级联反应，在器官大小控制中起重要作用。作为 Hippo 通路的主要效应子，转录共激活因子 Yap1/Wwtr1 受上游激酶 Stk3 的调节。最近对哺乳动物的研究表明 Hippo 通路与肾脏发育和肾脏疾病有关。为了进一步说明其在脊椎动物肾脏中的作用，我们生成了一系列针对 stk3、yap1 和 wwtr1 基因的斑马鱼突变体。stk3-/- 突变体在幼虫期表现出水肿、肾小球囊肿形成和前肾小管扩张。有趣的是，破坏 wwtr1 而不是 yap1 显着减轻了 stk3-/- 突变体的肾表型，并且 Wwtr1 与 CMV 启动子的过表达也在幼虫期诱导了肾前体表型，类似于 stk3-/- 突变体。尤其，Wwtr1 过表达的成年鱼发展出与人类多囊肾病 (PKD) 相似的表型。总体而言，我们的研究揭示了 Stk3 和 Wwtr1 在肾囊肿形成中的作用。使用药理学方法，我们进一步证明了 Stk3 缺陷斑马鱼可以作为药物开发的 PKD 模型。 |
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