Journal
DIABETES
Volume 67, Issue 1, Pages 58-70Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db16-1587
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Funding
- Ragnar Soderberg Foundation
- Swedish Research Council
- Swedish Foundation for Strategic Research
- Wenner-Gren Foundation
- Novo Nordisk Foundation
- Strategic Research Programme in Diabetes
- European Foundation for the Study of Diabetes/Lilly Fellowship
- Stem Cell Research and Regenerative Medicine at the Karolinska Institutet
- Novo Nordisk Fonden [NNF14OC0010717] Funding Source: researchfish
- Novo Nordisk Foundation Section for Basic Stem Cell Biology [Serup Group NNF] Funding Source: researchfish
- European Foundation for the Study of Diabetes [Lilly FS 2017_7] Funding Source: researchfish
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U54DK110858] Funding Source: NIH RePORTER
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Inhibition of notch signaling is known to induce differentiation of endocrine cells in zebrafish and mouse. After performing an unbiased in vivo screen of similar to 2,200 small molecules in zebrafish, we identified an inhibitor of Cdk5 (roscovitine), which potentiated the formation of beta-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 beta-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 beta-cell differentiation by genetic means. Moreover, the cdk5 mutant zebrafish displayed an increased number of beta-cells independently of inhibition of notch signaling, in both the basal state and during beta-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote beta-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 beta-cell differentiation and thereby further highlighted its importance in diabetes.
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