Inhibition of Cdk5 Promotes ß-Cell Differentiation From Ductal Progenitors.
Diabetes
; 67(1): 58-70, 2018 01.
Article
em En
| MEDLINE
| ID: mdl-28986398
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 â¼2,200 small molecules in zebrafish, we identified an inhibitor of Cdk5 (roscovitine), which potentiated the formation of ß-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 ß-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 ß-cell differentiation by genetic means. Moreover, the cdk5 mutant zebrafish displayed an increased number of ß-cells independently of inhibition of notch signaling, in both the basal state and during ß-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote ß-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 ß-cell differentiation and thereby further highlighted its importance in diabetes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ductos Pancreáticos
/
Células-Tronco
/
Células Secretoras de Insulina
/
Quinase 5 Dependente de Ciclina
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article