ZFIN ID: ZDB-PUB-171008-2
Inhibition of Cdk5 Promotes β-cell Differentiation from Ductal Progenitors
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.
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
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.