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 -
