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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