Dataset Information

Inhibition of Cdk5 Promotes ?-Cell Differentiation From Ductal Progenitors.

ABSTRACT: 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 ?-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 ?-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 ?-cell differentiation by genetic means. Moreover, the cdk5 mutant zebrafish displayed an increased number of ?-cells independently of inhibition of notch signaling, in both the basal state and during ?-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote ?-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 ?-cell differentiation and thereby further highlighted its importance in diabetes.

SUBMITTER: Liu KC

PROVIDER: S-EPMC6463766 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors.

Liu Ka-Cheuk KC Leuckx Gunter G Sakano Daisuke D Seymour Philip A PA Mattsson Charlotte L CL Rautio Linn L Staels Willem W Verdonck Yannick Y Serup Palle P Kume Shoen S Heimberg Harry H Andersson Olov O

Diabetes 20171006 1

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 ...[more]

PMID: 28986398

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Project description:Insulin-producing pancreatic islet beta cells (beta-cells) are destroyed, severely depleted or functionally impaired in diabetes. Therefore, replacing functional beta-cell mass would advance clinical diabetes management. We have previously demonstrated the importance of Cdk4 in regulating beta-cell mass. Cdk4-deficient mice display beta-cell hypoplasia and develop diabetes, whereas beta-cell hyperplasia is observed in mice expressing an active Cdk4R24C kinase. While beta-cell replication appears to be the primary mechanism responsible for beta-cell mass increase, considerable evidence also supports a contribution from the pancreatic ductal epithelium in generation of new beta-cells. Further, while it is believed that majority of beta-cells are in a state of 'dormancy', it is unclear if and to what extent the quiescent cells can be coaxed to participate in the beta-cell regenerative response. Here, we address these queries using a model of partial pancreatectomy (PX) in Cdk4 mutant mice. To investigate the kinetics of the regeneration process precisely, we performed DNA analog-based lineage-tracing studies followed by mathematical modeling. Within a week after PX, we observed considerable proliferation of islet beta-cells and ductal epithelial cells. Interestingly, the mathematical model showed that recruitment of quiescent cells into the active cell cycle promotes beta-cell mass reconstitution in the Cdk4R24C pancreas. Moreover, within 24-48 hours post-PX, ductal epithelial cells expressing the transcription factor Pdx-1 dramatically increased. We also detected insulin-positive cells in the ductal epithelium along with a significant increase of islet-like cell clusters in the Cdk4R24C pancreas. We conclude that Cdk4 not only promotes beta-cell replication, but also facilitates the activation of beta-cell progenitors in the ductal epithelium. In addition, we show that Cdk4 controls beta-cell mass by recruiting quiescent cells to enter the cell cycle. Comparing the contribution of cell proliferation and islet-like clusters to the total increase in insulin-positive cells suggests a hitherto uncharacterized large non-proliferative contribution.

Dataset Information

Inhibition of Cdk5 Promotes ?-Cell Differentiation From Ductal Progenitors.

Publications

Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors.

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