期刊
DEVELOPMENT
卷 144, 期 14, 页码 2595-2605出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.147397
关键词
Biliary atresia; Intrahepatic biliary network; Actin dynamics; Biliary epithelial cells; Cdk5r1a
资金
- National Institutes of Health (NIH) [R00 DK078138, RO1 DK103637]
- Cleveland Digestive Diseases Research Core Center - NIH [P30DK084576]
- Lerner Research Institute Chair's Innovation Research Fund
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.
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