PUBLICATION
Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish
- Authors
- Dimri, M., Bilogan, C., Pierce, L.X., Naegele, G., Vasanji, A., Gibson, I., McClendon, A., Tae, K., Sakaguchi, T.F.
- ID
- ZDB-PUB-170720-3
- Date
- 2017
- Source
- Development (Cambridge, England) 144: 2595-2605 (Journal)
- Registered Authors
- Pierce, Lain, Sakaguchi, Takuya
- Keywords
- Actin dynamics, Biliary atresia, Biliary epithelial cells, Cdk5r1a, Intrahepatic biliary network
- MeSH Terms
-
- Actin Depolymerizing Factors/metabolism
- Algorithms
- Animals
- Animals, Genetically Modified
- Bile Ducts, Intrahepatic/enzymology*
- Bile Ducts, Intrahepatic/growth & development*
- Computer Simulation
- Cyclin-Dependent Kinase 5/antagonists & inhibitors
- Cyclin-Dependent Kinase 5/genetics
- Cyclin-Dependent Kinase 5/metabolism*
- Gene Knockout Techniques
- Imaging, Three-Dimensional
- Larva/growth & development
- Larva/metabolism
- Lim Kinases/metabolism
- Models, Anatomic
- Morphogenesis/drug effects
- Morphogenesis/genetics
- Morphogenesis/physiology
- Mutation
- Protein Kinase Inhibitors/pharmacology
- Signal Transduction
- Zebrafish/genetics
- Zebrafish/growth & development*
- Zebrafish/metabolism*
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- p21-Activated Kinases/metabolism
- PubMed
- 28720653 Full text @ Development
Citation
Dimri, M., Bilogan, C., Pierce, L.X., Naegele, G., Vasanji, A., Gibson, I., McClendon, A., Tae, K., Sakaguchi, T.F. (2017) Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish. Development (Cambridge, England). 144:2595-2605.
Abstract
The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish. Further, we identified a previously unappreciated downstream kinase cascade regulated by Cdk5. Pharmacological manipulations of this downstream kinase cascade produced a crowded branching defect in the intrahepatic biliary network and influenced actin dynamics in biliary epithelial cells. We generated larvae carrying a mutation in cdk5 regulatory subunit 1a (cdk5r1a), an essential activator of Cdk5. cdk5r1a mutant larvae show similar branching defects as those observed in Cdk5 inhibitor-treated larvae. A small-molecule compound that interferes with the downstream kinase cascade rescued the mutant phenotype. These results provide new insights into branching morphogenesis of the intrahepatic biliary network.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping