Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish

Manali Dimri, Cassandra Bilogan, Lain X. Pierce, Gregory Naegele, Amit Vasanji, Isabel Gibson, Allyson McClendon, Kevin Tae, Takuya F. Sakaguchi

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)2595-2605
Number of pages11
JournalDevelopment (Cambridge)
Volume144
Issue number14
DOIs
StatePublished - Jul 15 2017
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 5
Zebrafish
Phosphotransferases
Larva
Liver
Epithelial Cells
Morphogenesis
Actins
Pharmacology
Phenotype
Mutation

Keywords

  • Actin dynamics
  • Biliary atresia
  • Biliary epithelial cells
  • Cdk5r1a
  • Intrahepatic biliary network

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish. / Dimri, Manali; Bilogan, Cassandra; Pierce, Lain X.; Naegele, Gregory; Vasanji, Amit; Gibson, Isabel; McClendon, Allyson; Tae, Kevin; Sakaguchi, Takuya F.

In: Development (Cambridge), Vol. 144, No. 14, 15.07.2017, p. 2595-2605.

Research output: Contribution to journalArticle

Dimri, M, Bilogan, C, Pierce, LX, Naegele, G, Vasanji, A, Gibson, I, McClendon, A, Tae, K & Sakaguchi, TF 2017, 'Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish', Development (Cambridge), vol. 144, no. 14, pp. 2595-2605. https://doi.org/10.1242/dev.147397
Dimri, Manali ; Bilogan, Cassandra ; Pierce, Lain X. ; Naegele, Gregory ; Vasanji, Amit ; Gibson, Isabel ; McClendon, Allyson ; Tae, Kevin ; Sakaguchi, Takuya F. / Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish. In: Development (Cambridge). 2017 ; Vol. 144, No. 14. pp. 2595-2605.
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