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

Onderzoeksoutput: Articlepeer review

25 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)58-70
Aantal pagina's13
TijdschriftDiabetes
Volume67
Nummer van het tijdschrift1
DOI's
StatusPublished - jan 2018

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