Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions

  1. Kenneth S. Zaret1
  1. 1Institute for Regenerative Medicine, Institute for Diabetes Obesity and Metabolism, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
  2. 2Department of Surgery, University of Pennsylvania Perelman School of Medicine, Smilow Center for Translational Research, Philadelphia, PA
  1. Corresponding author: Kenneth S. Zaret, zaret{at}upenn.edu.

Abstract

In the pancreas, α- and β-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly α- and polyhormonal β-like cells, indicating a gap in understanding of how functional monohormonal β-cells are formed and of the endogenous repressive mechanisms used to maintain β-cell identity. We show that the corepressor Grg3 is expressed in almost all β-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent α-cells and is progressively lost from α-cells as endocrine cells mature into adulthood. We show that mouse Grg3+/− β-cells have increased α-specific gene expression, and Grg3+/− pancreata have more α-cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal β-cell identity. Ectopic expression of Grg3 in α-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human β-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal β-cell identity, and Groucho family members may be useful tools or markers for making functional β-cells.

Footnotes

  • Received May 31, 2013.
  • Accepted January 26, 2014.

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  1. Diabetes vol. 63 no. 5 1804-1816
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