Regulation of the Pancreatic Pro-Endocrine Gene Neurogenin3

Abstract

Neurogenin3 (ngn3), a basic helix-loop-helix (bHLH) transcription factor, functions as a pro-endocrine factor in the developing pancreas: by itself, it is sufficient to force undifferentiated pancreatic epithelial cells to become islet cells. Because ngn3 expression determines which precursor cells will differentiate into islet cells, the signals that regulate ngn3 expression control islet cell formation. To investigate the factors that control ngn3 gene expression, we mapped the human and mouse ngn3 promoters and delineated transcriptionally active sequences within the human promoter. Surprisingly, the human ngn3 promoter drives transcription in all cell lines tested, including fibroblast cell lines. In contrast, in transgenic animals the promoter drives expression specifically in regions of ngn3 expression in the developing pancreas and gut; and the addition of distal sequences greatly enhances transgene expression. Within the distal enhancer, binding sites for several pancreatic transcription factors, including hepatocyte nuclear factor (HNF)-1 and HNF-3, form a tight cluster. HES1, an inhibitory bHLH factor activated by Notch signaling, binds to the proximal promoter and specifically blocks promoter activity. Together with previous genetic data, these results suggest a model in which the ngn3 gene is activated by the coordinated activities of several pancreatic transcription factors and inhibited by Notch signaling through HES1. Diabetes 50:928 -936, 2001

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

“…Downregulation of FOXO1 mRNA in human fetal islets resulted in a significant upregulation of NGN3 mRNA levels and the number of NGN3 + cells, suggesting that NGN3 may be a potential target for FOXO1. In support of this, a cluster of binding sites for forkhead factors, including FOXA2, was recently identified in the distal region of the NGN3 promoter [16]. In murine adult islets, FOXA2 competes with FOXO1 for the same binding site within the Pdx-1 promoter to regulate Pdx-1 expression [7].…”

“…More recently, FOXO1 has been reported in murine myoblasts to interact with Notch signalling to regulate hairy and enhancer of split 1 (Hes1) gene expression; HES1 is a well-known repressor of neurogenin 3 (Ngn3 [also known as Neurog3]) [15,16]. These findings suggest that FOXO1 may be involved at multiple steps of murine pancreatic organogenesis [12].…”

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

“…Luciferase assays next demonstrated that SOX4 can transactivate a 2 kb fragment of the Neurog3 promoter (Fig. 4c) [43]. Collectively, these results suggest that SOX4 expression within a subset of bipotent trunk progenitors enhances NEUROG3 expression and drives subsequent endocrine progenitor cell formation.…”

Efficient restricted gene expression in beta cells by lentivirus-mediated gene transfer into pancreatic stem/progenitor cells

“…There are different arguments indicating that pancreatic progenitor cells are located in the centre of the pancreatic tissue: (1) during embryonic life, the cells expressing ngn3, a marker of endocrine pancreatic progenitor cells, are located in the central region of the developing pancreas that corresponds to the pancreatic epithelium [36,[44][45][46]; (2) the first insulin-expressing cells also appear in the central region of the pancreas [47]. However, it is well established that in compact tissues, the accessibility of viral particles to cells located in the centre of the tissue is poor [3].…”