Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors

TY - JOUR

T1 - Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors

AU - Liu, Ka-Cheuk

AU - Leuckx, Gunter

AU - Sakano, Daisuke

AU - Seymour, Philip A

AU - Mattsson, Charlotte L

AU - Rautio, Linn

AU - Staels, Willem

AU - Verdonck, Yannick

AU - Serup, Palle

AU - Kume, Shoen

AU - Heimberg, Harry

AU - Andersson, Olov

N1 - © 2017 by the American Diabetes Association.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation/genetics

KW - Cyclin-Dependent Kinase 5/genetics

KW - Genome-Wide Association Study

KW - Genotype

KW - Insulin-Secreting Cells/cytology

KW - Larva/cytology

KW - Pancreatic Ducts/cytology

KW - Real-Time Polymerase Chain Reaction

KW - Signal Transduction/physiology

KW - Stem Cells/cytology

KW - Zebrafish/genetics

KW - Zebrafish Proteins/genetics

U2 - 10.2337/db16-1587

DO - 10.2337/db16-1587

M3 - Journal article

C2 - 28986398

SN - 0012-1797

VL - 67

SP - 58

EP - 70

JO - Diabetes

JF - Diabetes

IS - 1

ER -