Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish
| Autor: | Isabel Gibson, Gregory Naegele, Amit Vasanji, Takuya F. Sakaguchi, Manali Dimri, Lain X. Pierce, Allyson McClendon, Kevin Tae, Cassandra Bilogan |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Models
Anatomic 0301 basic medicine Protein subunit Mutant Biology medicine.disease_cause Animals Genetically Modified Gene Knockout Techniques 03 medical and health sciences Imaging Three-Dimensional Biliary atresia Morphogenesis medicine Animals Computer Simulation Protein Kinase Inhibitors Molecular Biology Zebrafish Mutation Kinase Activator (genetics) Cyclin-dependent kinase 5 Lim Kinases Cyclin-Dependent Kinase 5 Cell Biology Anatomy Zebrafish Proteins medicine.disease biology.organism_classification Cell biology Bile Ducts Intrahepatic 030104 developmental biology Actin Depolymerizing Factors p21-Activated Kinases nervous system Biochemistry Larva Algorithms Signal Transduction Research Article Developmental Biology |
| Zdroj: | Development. 144:2595-2605 |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.147397 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|