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Cell Metab. 2014 Feb 4;19(2):259-71. doi: 10.1016/j.cmet.2013.12.002.

Pdx1 maintains β cell identity and function by repressing an α cell program.

Author information

1
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.
2
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
3
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Endocrinology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Umea Centre for Molecular Medicine, Umea University, SE-901 87 Umea, Sweden.
8
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.

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.

PMID:
24506867
PMCID:
PMC3950964
DOI:
10.1016/j.cmet.2013.12.002
[Indexed for MEDLINE]
Free PMC Article

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