Inhibition of Cdk5 Promotes β-cell Differentiation from Ductal Progenitors

Ka-Cheuk Liu, Gunter Leuckx, Daisuke Sakano, Philip A Seymour, Charlotte L Mattsson, Linn Rautio, Willem Staels, Yannick Verdonck, Palle Serup, Shoen Kume, Henry Heimberg, Olov Andersson

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Inhibition of notch signaling is known to induce differentiation of endocrine cells in zebrafish and mouse. After performing an unbiased in vivo screen of ∼2,200 small molecules in zebrafish, we identified an inhibitor of Cdk5 (roscovitine), which potentiated the formation of β-cells along the intrapancreatic duct during concurrent inhibition of notch signaling. We confirmed and characterized the effect with a more selective Cdk5 inhibitor, (R)-DRF053, which specifically increased the number of duct-derived β-cells without affecting their proliferation. By duct-specific overexpression of the endogenous Cdk5 inhibitors Cdk5rap1 or Cdkal1 (which previously have been linked to diabetes in genome-wide association studies), as well as deleting cdk5, we validated the role of chemical Cdk5 inhibition in b-cell differentiation by genetic means. Moreover, the cdk5 mutant zebrafish displayed an increased number of β-cells independently of inhibition of notch signaling, in both the basal state and during b-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote b-cell formation was conserved in mouse embryonic pancreatic explants, adult mice with pancreatic ductal ligation injury, and human induced pluripotent stem (iPS) cells. Thus, we have revealed a previously unknown role of Cdk5 as an endogenous suppressor of b-cell differentiation and thereby further highlighted its importance in diabetes.

Original languageEnglish
Pages (from-to)58-70
Number of pages13
JournalDiabetes
Volume67
Issue number1
DOIs
Publication statusPublished - Jan 2018

Keywords

  • Journal Article
  • beta cell
  • duct cell
  • differentiation
  • cell cycle
  • Cdk5
  • roscovitine
  • mouse embryo
  • partial duct ligation
  • iPScells
  • Genome-Wide Association Study
  • Larva/cytology
  • Insulin-Secreting Cells/cytology
  • Cyclin-Dependent Kinase 5/genetics
  • Genotype
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Signal Transduction/physiology
  • Animals
  • Pancreatic Ducts/cytology
  • Cell Differentiation/genetics
  • Real-Time Polymerase Chain Reaction
  • Stem Cells/cytology

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