Regulation of the pancreatic pro-endocrine gene neurogenin3

Jane C. Lee, Stewart B. Smith, Hirotaka Watada, Joseph Lin, David Scheel, Juehu Wang, Raghavendra G. Mirmira, Michael S. German

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197 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)928-936
Number of pages9
JournalDiabetes
Volume50
Issue number5
DOIs
StatePublished - Jan 1 2001

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Lee, J. C., Smith, S. B., Watada, H., Lin, J., Scheel, D., Wang, J., Mirmira, R. G., & German, M. S. (2001). Regulation of the pancreatic pro-endocrine gene neurogenin3. Diabetes, 50(5), 928-936. https://doi.org/10.2337/diabetes.50.5.928