title: Foxa1 and Foxa2 regulate α-cell differentiation, glucagon biosynthesis, and secretion.
abstract: 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.
authors: Department of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital of Geneva, Medical School, 1211 Geneva 14, Switzerland.
authors: Mounia
authors: M
authors: Heddad Masson
authors: Caroline
authors: C
authors: Poisson
authors: Audrey
authors: A
authors: Guérardel
authors: Aline
authors: A
authors: Mamin
authors: Jacques
authors: J
authors: Philippe
authors: Yvan
authors: Y
authors: Gosmain
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D006224:Cricetinae; D005934:Glucagon / Q000096:biosynthesis* / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000502:physiology*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D000090322:Homeobox Protein Nkx-2.2; D008297:Male; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats
chemical_list: C496501:Foxa1 protein, rat; C496504:Foxa2 protein, rat; D051541:Hepatocyte Nuclear Factor 3-alpha; D000090322:Homeobox Protein Nkx-2.2; C000715627:Nkx2-2 protein, mouse; C000715628:Nkx2-2 protein, rat; D034741:RNA, Small Interfering; D051542:Hepatocyte Nuclear Factor 3-beta; D005934:Glucagon