PUBLICATION
Core Hippo pathway components act as a brake on Yap/Taz in the development and maintenance of the biliary network
- Authors
- Brandt, Z.J., Echert, A.E., Bostrom, J.R., North, P.N., Link, B.A.
- ID
- ZDB-PUB-200524-5
- Date
- 2020
- Source
- Development (Cambridge, England) 147(12): (Journal)
- Registered Authors
- Link, Brian
- Keywords
- Cholangiocarcinoma, Gallbladder, Hepatopancreatic ductal system, Hippo pathway, Sav1, Stk3
- MeSH Terms
-
- Animals
- Animals, Genetically Modified/growth & development
- Animals, Genetically Modified/metabolism
- Biliary Tract/anatomy & histology
- Biliary Tract/growth & development
- Biliary Tract/metabolism*
- CRISPR-Cas Systems/genetics
- Carboxylic Ester Hydrolases/metabolism
- Gallbladder/anatomy & histology
- Gallbladder/growth & development
- Gallbladder/metabolism
- Larva/growth & development
- Larva/metabolism
- Liver/anatomy & histology
- Liver/metabolism
- Phenotype
- Protein Serine-Threonine Kinases/deficiency
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism*
- Signal Transduction
- Trans-Activators/genetics
- Trans-Activators/metabolism*
- Transcription Factors/genetics
- Transcription Factors/metabolism*
- Zebrafish/growth & development
- Zebrafish/metabolism
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 32439761 Full text @ Development
Citation
Brandt, Z.J., Echert, A.E., Bostrom, J.R., North, P.N., Link, B.A. (2020) Core Hippo pathway components act as a brake on Yap/Taz in the development and maintenance of the biliary network. Development (Cambridge, England). 147(12):.
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 allow 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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping