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Novel zebrafish polycystic kidney disease (PKD) models reveal functions of the Hippo pathway in renal cystogenesis.


ABSTRACT: 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.

SUBMITTER: Ren Z 

PROVIDER: S-EPMC8592019 | biostudies-literature |

REPOSITORIES: biostudies-literature

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