Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Diabetes |
Volume | 67 |
Issue number | 1 |
Pages (from-to) | 58-70 |
Number of pages | 13 |
ISSN | 0012-1797 |
DOIs | |
Publication status | Published - Jan 2018 |
- Animals, Cell Differentiation/genetics, Cyclin-Dependent Kinase 5/genetics, Genome-Wide Association Study, Genotype, Insulin-Secreting Cells/cytology, Larva/cytology, Pancreatic Ducts/cytology, Real-Time Polymerase Chain Reaction, Signal Transduction/physiology, Stem Cells/cytology, Zebrafish/genetics, Zebrafish Proteins/genetics
Research areas
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463766/pdf/db161587.pdf
Final published version
ID: 202029945