Pax6 is crucial for β-cell function, insulin biosynthesis, and glucose-induced insulin secretion
| Autor: | Yvan Gosmain, Jacques Philippe, Caroline Poisson, Liora S. Katz, Mounia Heddad Masson, Claire Cheyssac |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
PAX6 Transcription Factor
Transcription Genetic medicine.medical_treatment Repressor Proteins/genetics/metabolism/physiology Insulin-Secreting Cells/metabolism/physiology/secretion Mice Endocrinology Glucagon-Like Peptide 1 Insulin-Secreting Cells Insulin Secretion Gene expression Transcriptional regulation Insulin Paired Box Transcription Factors Lectins C-Type/genetics/metabolism Promoter Regions Genetic Cells Cultured Original Research Regulation of gene expression ddc:616 Gene knockdown Membrane Glycoproteins Paired Box Transcription Factors/genetics/metabolism/physiology Cell Differentiation General Medicine Glucose/physiology Insulin/biosynthesis/metabolism/secretion Cell biology Protein Precursors/biosynthesis/metabolism/secretion Homeodomain Proteins/genetics/metabolism/physiology Gene Knockdown Techniques PDX1 RNA Interference Insulin processing Protein Binding endocrine system Eye Proteins/genetics/metabolism/physiology Trans-Activators/genetics/metabolism Biology medicine Membrane Glycoproteins/genetics/metabolism Animals Lectins C-Type Protein Precursors Eye Proteins Molecular Biology Homeodomain Proteins Binding Sites Base Sequence Gene Expression Profiling Glucagon-Like Peptide 1/physiology Molecular biology eye diseases Rats Repressor Proteins Glucose Gene Expression Regulation Trans-Activators biology.protein GLUT2 sense organs Protein Processing Post-Translational |
| Zdroj: | Molecular Endocrinology, Vol. 26, No 4 (2012) pp. 696-709 |
| ISSN: | 0888-8809 |
| Popis: | The Pax6 transcription factor is crucial for endocrine cell differentiation and function. Indeed, mutations of Pax6 are associated with a diabetic phenotype and a drastic decrease of insulin-positive cell number. Our aim was to better define the β-cell Pax6 transcriptional network and thus provide further information concerning the role of Pax6 in β-cell function. We developed a Pax6-deficient model in rat primary β-cells with specific small interfering RNA leading to a 75% knockdown of Pax6 expression. Through candidate gene approach, we confirmed that Pax6 controls the mRNA levels of the insulin 1 and 2, Pdx1, MafA, GLUT2, and PC1/3 genes in β-cells. Importantly, we identified new Pax6 target genes coding for GK, Nkx6.1, cMaf, PC2, GLP-1R and GIPR which are all involved in β-cell function. Furthermore, we demonstrated that Pax6 directly binds and activates specific elements on the promoter region of these genes. We also demonstrated that Pax6 knockdown led to decreases in insulin cell content, in insulin processing, and a specific defect of glucose-induced insulin secretion as well as a significant reduction of GLP-1 action in primary β-cells. Our results strongly suggest that Pax6 is crucial for β-cells through transcriptional control of key genes coding for proteins that are involved in insulin biosynthesis and secretion as well as glucose and incretin actions on β-cells. We provide further evidence that Pax6 represents a key element of mature β-cell function. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|