Grg3/TLE3 and Grg1/TLE1 induce monohormonal pancreatic β-cells while repressing α-cell functions.
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.
Institute for Regenerative Medicine, Institute for Diabetes Obesity and Metabolism, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
David E
DE
Metzger
Chengyang
C
Liu
Amin Sam
AS
Ziaie
Ali
A
Naji
Kenneth S
KS
Zaret
D000818:Animals; D002454:Cell Differentiation; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C469265:ARX protein, mouse; D056970:Co-Repressor Proteins; D018398:Homeodomain Proteins; C434946:Tle1 protein, mouse; C104849:Tle3 protein, mouse; D014157:Transcription Factors; D005934:Glucagon