Sox9 coordinates a transcriptional network in pancreatic progenitor cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 25; pp. 10500 - 10505
• Main Authors: Lynn, F.C, Smith, S.B, Wilson, M.E, Yang, K.Y, Nekrep, N, German, M.S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.06.2007; National Acad Sciences
• Subjects: Animals; Binding Sites; Biological Sciences; Cell Line; Cell lines; Cells; Cellular differentiation; DNA; Embryology; Endocrine cells; Endocrine system; Gene expression; Gene Regulatory Networks - physiology; Genes, Reporter; High Mobility Group Proteins - genetics; High Mobility Group Proteins - metabolism; Immunohistochemistry; Islets of Langerhans; Luciferases - metabolism; Mice; Mice, Inbred Strains; Models, Biological; Neural stem cells; Neurons; Pancreas; Pancreas - cytology; Pancreatic cells; Progenitor cells; RNA Interference; Rodents; SOX9 Transcription Factor; Stem Cells - metabolism; Stem Cells - physiology; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0704054104

During pancreas development, both the exocrine and endocrine lineages differentiate from a common pool of progenitor cells with similarities to mature pancreatic duct cells. A small set of transcription factors, including Tcf2, Onecut1, and Foxa2, has been identified in these pancreatic progenitor cells. The Sry/HMG box transcription factor Sox9 is also expressed in the early pancreatic epithelium and is required for normal pancreatic exocrine and endocrine development in humans. In this study, we found Sox9 in mice specifically expressed with the other progenitor transcription factors in both pancreatic progenitor cells and duct cells in the adult pancreas. Sox9 directly bound to all three genes in vitro and in intact cells, and regulated their expression. In turn, both Foxa2 and Tcf2 regulated Sox9 expression, demonstrating feedback circuits between these genes. Furthermore, Sox9 activated the expression of the proendocrine factor Neurogenin3, which also depends on the other members of the progenitor transcription network. These studies indicate that Sox9 plays a dual role in pancreatic progenitor cells: both maintaining a stable transcriptional network and supporting the programs by which these cells differentiate into distinct lineages.