000154702 001__ 154702
000154702 005__ 20181203022100.0
000154702 0247_ $$2doi$$a10.2337/db09-0986
000154702 022__ $$a1939-327X
000154702 02470 $$2ISI$$a000279615100016
000154702 037__ $$aARTICLE
000154702 245__ $$aThe transcription factor Rfx3 regulates beta-cell differentiation, function, and glucokinase expression
000154702 260__ $$bAmerican Diabetes Association$$c2010
000154702 269__ $$a2010
000154702 336__ $$aJournal Articles
000154702 520__ $$aOBJECTIVE: Pancreatic islets of perinatal mice lacking the transcription factor Rfx3 exhibit a marked reduction in insulin-producing beta-cells. The objective of this work was to unravel the cellular and molecular mechanisms underlying this deficiency. RESEARCH DESIGN AND METHODS: Immunofluorescence studies and quantitative RT-PCR experiments were used to study the emergence of insulin-positive cells, the expression of transcription factors implicated in the differentiation of beta-cells from endocrine progenitors, and the expression of mature beta-cell markers during development in Rfx3(-/-) and pancreas-specific Rfx3-knockout mice. RNA interference experiments were performed to document the consequences of downregulating Rfx3 expression in Min6 beta-cells. Quantitative chromatin immunoprecipitation (ChIP), ChIP sequencing, and bandshift experiments were used to identify Rfx3 target genes. RESULTS: Reduced development of insulin-positive cells in Rfx3(-/-) mice was not due to deficiencies in endocrine progenitors or beta-lineage specification, but reflected the accumulation of insulin-positive beta-cell precursors and defective beta-cells exhibiting reduced insulin, Glut-2, and Gck expression. Similar incompletely differentiated beta-cells developed in pancreas-specific Rfx3-deficient embryos. Defective beta-cells lacking Glut-2 and Gck expression dominate in Rfx3-deficent adults, leading to glucose intolerance. Attenuated Glut-2 and glucokinase expression, and impaired glucose-stimulated insulin secretion, were also induced by RNA interference-mediated inhibition of Rfx3 expression in Min6 cells. Finally, Rfx3 was found to bind in Min6 cells and human islets to two well-known regulatory sequences, Pal-1 and Pal-2, in the neuroendocrine promoter of the glucokinase gene. CONCLUSIONS: Our results show that Rfx3 is required for the differentiation and function of mature beta-cells and regulates the beta-cell promoter of the glucokinase gene.
000154702 6531_ $$aStimulated Insulin-Secretion
000154702 6531_ $$aDna-Binding Proteins
000154702 6531_ $$aEmbryonic Stem-Cells
000154702 6531_ $$aLeft-Right Asymmetry
000154702 6531_ $$aPancreas Development
000154702 6531_ $$aEndocrine Pancreas
000154702 6531_ $$aMotor Protein
000154702 6531_ $$aMice Lacking
000154702 6531_ $$aGene
000154702 6531_ $$aPromoter
000154702 700__ $$aAit-Lounis, Aouatef
000154702 700__ $$aBonal, Claire
000154702 700__ $$aSeguín-Estévez, Queralt
000154702 700__ $$aSchmid, Christoph D.
000154702 700__ $$0244404$$aBucher, Philipp$$g113607
000154702 700__ $$aHerrera, Pedro L.
000154702 700__ $$aDurand, Bénédicte
000154702 700__ $$aMeda, Paolo
000154702 700__ $$aReith, Walter
000154702 773__ $$j59$$k7$$q1674-85$$tDiabetes
000154702 909C0 $$0252244$$pGR-BUCHER$$xU11780
000154702 909CO $$ooai:infoscience.tind.io:154702$$pSV$$particle
000154702 917Z8 $$x182396
000154702 937__ $$aEPFL-ARTICLE-154702
000154702 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000154702 980__ $$aARTICLE