Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β Cells While Repressing α Cell Functions
- 1Institute for Regenerative Medicine, Institute for Diabetes Obesity and Metabolism, Department of Cell and Developmental Biology and
- 2Department of Surgery, University of Pennsylvania Perelman School of Medicine, Smilow Center for Translational Research, 3400 Civic Center Blvd, Philadelphia, PA 19104
- *Corresponding Author: Dr. Ken Zaret,
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 the endogenous repressive mechanisms used to maintain β cell identity. Here, 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 further 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 similar 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.
- Received March 31, 2013.
- Accepted January 22, 2014.
- © 2014 by the American Diabetes Association.
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