title: Pdx1 maintains β cell identity and function by repressing an α cell program.
abstract: Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult β cell function. In this study, we traced the fate of adult β cells after Pdx1 deletion. As expected, β-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of α cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift that included derepression of the α cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of α cells. These findings indicate that Pdx1 acts as a master regulator of β cell fate by simultaneously activating genes essential for β cell identity and repressing those associated with α cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of β cell identity contributes to the pathogenesis of type 2 diabetes.
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Tao
authors: T
authors: Gao
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Brian
authors: B
authors: McKenna
authors: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Changhong
authors: C
authors: Li
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Maximilian
authors: M
authors: Reichert
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: James
authors: J
authors: Nguyen
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Tarjinder
authors: T
authors: Singh
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Chenghua
authors: C
authors: Yang
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Archana
authors: A
authors: Pannikar
authors: Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Nicolai
authors: N
authors: Doliba
authors: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Tingting
authors: T
authors: Zhang
authors: Endocrinology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Doris A
authors: DA
authors: Stoffers
authors: Umea Centre for Molecular Medicine, Umea University, SE-901 87 Umea, Sweden.
authors: Helena
authors: H
authors: Edlund
authors: Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Franz
authors: F
authors: Matschinsky
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Roland
authors: R
authors: Stein
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bstanger@exchange.upenn.edu.
authors: Ben Z
authors: BZ
authors: Stanger
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051258:MafB Transcription Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D051258:MafB Transcription Factor; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein