Islet-1 Is essential for pancreatic ß-cell function.
Diabetes
; 63(12): 4206-17, 2014 Dec.
Article
en En
| MEDLINE
| ID: mdl-25028525
ABSTRACT
Islet-1 (Isl-1) is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal ß-cell by performing physiological and morphometric analyses of a tamoxifen-inducible, ß-cell-specific Isl-1 loss-of-function mouse Isl-1(L/L); Pdx1-CreER(Tm). Ablating Isl-1 in postnatal ß-cells reduced glucose tolerance without significantly reducing ß-cell mass or increasing ß-cell apoptosis. Rather, islets from Isl-1(L/L); Pdx1-CreER(Tm) mice showed impaired insulin secretion. To identify direct targets of Isl-1, we integrated high-throughput gene expression and Isl-1 chromatin occupancy using islets from Isl-1(L/L); Pdx1-CreER(Tm) mice and ßTC3 insulinoma cells, respectively. Ablating Isl-1 significantly affected the ß-cell transcriptome, including known targets Insulin and MafA as well as novel targets Pdx1 and Slc2a2. Using chromatin immunoprecipitation sequencing and luciferase reporter assays, we found that Isl-1 directly occupies functional regulatory elements of Pdx1 and Slc2a2. Thus Isl-1 is essential for postnatal ß-cell function, directly regulates Pdx1 and Slc2a2, and has a mature ß-cell cistrome distinct from that of pancreatic endocrine progenitors.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Resistencia a la Insulina
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Células Secretoras de Insulina
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Elementos Reguladores de la Transcripción
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Proteínas con Homeodominio LIM
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Diabetes
Año:
2014
Tipo del documento:
Article
País de afiliación:
Panamá