Inhibition of Cdk5 Promotes β-cell Differentiation from Ductal Progenitors.

Inhibition of Cdk5 Promotes β-cell Differentiation from Ductal Progenitors.

Diabetes. 2017 Oct 06;:

Authors: Liu KC, Leuckx G, Sakano D, Seymour PA, Mattsson CL, Rautio L, Staels W, Verdonck Y, Serup P, Kume S, Heimberg H, Andersson O

Abstract
Inhibition of notch signalling is known to induce differentiation of endocrine cells in zebrafish and mouse. After performing an unbiased in vivo screen of ∼2200 small molecules in zebrafish we identified an inhibitor of Cdk5 (roscovitine), which potentiated formation of β-cells along the intra-pancreatic duct during concurrent inhibition of notch signalling. 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 GWAS), 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 signalling, 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 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.

PMID: 28986398 [PubMed - as supplied by publisher]

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