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.
Original language | English (US) |
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Pages (from-to) | 2595-2605 |
Number of pages | 11 |
Journal | Development (Cambridge) |
Volume | 144 |
Issue number | 14 |
DOIs | |
State | Published - Jul 15 2017 |
Keywords
- Actin dynamics
- Biliary atresia
- Biliary epithelial cells
- Cdk5r1a
- Intrahepatic biliary network
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology