|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.
|Source:||Development (Cambridge, England) 144: 2595-2605 (Journal)|
|Registered Authors:||Sakaguchi, Takuya|
|Keywords:||Actin dynamics, Biliary atresia, Biliary epithelial cells, Cdk5r1a, Intrahepatic biliary network|
|PubMed:||28720653 Full text @ Development|
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.
ABSTRACTThe 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.