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Core Hippo pathway components act as a brake on Yap and Taz in the development and maintenance of the biliary network.

ABSTRACT: The development of the biliary system is a complex yet poorly understood process, with relevance to multiple diseases, including biliary atresia, choledochal cysts and gallbladder agenesis. We present here a crucial role for Hippo-Yap/Taz signaling in this context. Analysis of sav1 mutant zebrafish revealed dysplastic morphology and expansion of both intrahepatic and extrahepatic biliary cells, and ultimately larval lethality. Biliary dysgenesis, but not larval lethality, is driven primarily by Yap signaling. Re-expression of Sav1 protein in sav1 ^-/- hepatocytes is able to overcome these initial deficits and allows sav1 ^-/- fish to survive, suggesting cell non-autonomous signaling from hepatocytes. Examination of sav1 ^-/- rescued adults reveals loss of gallbladder and formation of dysplastic cell masses expressing biliary markers, suggesting roles for Hippo signaling in extrahepatic biliary carcinomas. Deletion of stk3 revealed that the phenotypes observed in sav1 mutant fish function primarily through canonical Hippo signaling and supports a role for phosphatase PP2A, but also suggests Sav1 has functions in addition to facilitating Stk3 activity. Overall, this study defines a role for Hippo-Yap signaling in the maintenance of both intra- and extrahepatic biliary ducts.

SUBMITTER: Brandt ZJ

PROVIDER: S-EPMC7328147 | biostudies-literature |

REPOSITORIES: biostudies-literature

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