ZFIN ID: ZDB-PUB-170720-3
Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish
Dimri, M., Bilogan, C., Pierce, L.X., Naegele, G., Vasanji, A., Gibson, I., McClendon, A., Tae, K., Sakaguchi, T.F.
Date: 2017
Source: Development (Cambridge, England)   144: 2595-2605 (Journal)
Registered Authors: 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
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.