Foxa1 and Foxa2 Regulate α-Cell Differentiation, Glucagon Biosynthesis, and Secretion
| Autor: | Caroline Poisson, Audrey Guérardel, Jacques Philippe, Mounia Heddad Masson, Yvan Gosmain, Aline Mamin |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Hepatocyte Nuclear Factor 3-alpha
Male endocrine system medicine.medical_specialty Glucagon/biosynthesis/secretion Cellular differentiation Cell Differentiation/drug effects/genetics Hepatocyte Nuclear Factor 3-alpha/antagonists & inhibitors/physiology 030209 endocrinology & metabolism Biology RNA Small Interfering/pharmacology Binding Sites/genetics Glucagon 03 medical and health sciences 0302 clinical medicine Endocrinology Cricetinae Glucagon-Secreting Cells/physiology Internal medicine Gene expression medicine Animals Glucose homeostasis RNA Small Interfering Promoter Regions Genetic Transcription factor Cells Cultured reproductive and urinary physiology 030304 developmental biology ddc:616 0303 health sciences Binding Sites Glucagon secretion Cell Differentiation respiratory system Rats Homeobox Protein Nkx-2.2 Glucagon-Secreting Cells MAFB Hepatocyte Nuclear Factor 3-beta/antagonists & inhibitors/physiology embryonic structures Hepatocyte Nuclear Factor 3-beta FOXA2 |
| Zdroj: | Endocrinology, Vol. 155, No 10 (2014) pp. 3781-3792 Endocrinology |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2013-1843 |
| Popis: | The Forkhead box A transcription factors are major regulators of glucose homeostasis. They show both distinct and redundant roles during pancreas development and in adult mouse β-cells. In vivo ablation studies have revealed critical implications of Foxa1 on glucagon biosynthesis and requirement of Foxa2 in α-cell terminal differentiation. In order to examine the respective role of these factors in mature α-cells, we used small interfering RNA (siRNA) directed against Foxa1 and Foxa2 in rat primary pancreatic α-cells and rodent α-cell lines leading to marked decreases in Foxa1 and Foxa2 mRNA levels and proteins. Both Foxa1 and Foxa2 control glucagon gene expression specifically through the G2 element. Although we found that Foxa2 controls the expression of the glucagon, MafB, Pou3f4, Pcsk2, Nkx2.2, Kir6.2, and Sur1 genes, Foxa1 only regulates glucagon gene expression. Interestingly, the Isl1 and Gipr genes were not controlled by either Foxa1 or Foxa2 alone but by their combination. Foxa1 and Foxa2 directly activate and bind the promoter region the Nkx2.2, Kir6.2 and Sur1, Gipr, Isl1, and Pou3f4 genes. We also demonstrated that glucagon secretion is affected by the combined effects of Foxa1 and Foxa2 but not by either one alone. Our results indicate that Foxa1 and Foxa2 control glucagon biosynthesis and secretion as well as α-cell differentiation with both common and unique target genes. |
| Databáze: | OpenAIRE |
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