PUBLICATION

Inhibition of Cdk5 Promotes β-cell Differentiation from Ductal Progenitors

Authors
Liu, K.C., Leuckx, G., Sakano, D., Seymour, P.A., Mattsson, C.L., Rautio, L., Staels, W., Verdonck, Y., Serup, P., Kume, S., Heimberg, H., Andersson, O.
ID
ZDB-PUB-171008-2
Date
2017
Source
Diabetes   67(1): 58-70 (Journal)
Registered Authors
Anderson, Olov, Mattsson, Charlotte, Rautio, Linn
Keywords
none
MeSH Terms
  • Animals
  • Cell Differentiation/genetics
  • Cell Differentiation/physiology
  • Cyclin-Dependent Kinase 5/genetics
  • Cyclin-Dependent Kinase 5/metabolism*
  • Genome-Wide Association Study
  • Genotype
  • Insulin-Secreting Cells/cytology*
  • Insulin-Secreting Cells/metabolism*
  • Larva/cytology
  • Pancreatic Ducts/cytology*
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction/physiology
  • Stem Cells/cytology*
  • Stem Cells/metabolism*
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
28986398 Full text @ Diabetes
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 β-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 β-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote β-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 β-cell differentiation and thereby further highlighted its importance in diabetes.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Errata and Notes