Nkx6.1 regulates islet -cell proliferation via Nr4a1 and Nr4a3 nuclear receptors

Loss of functional -cell mass is a hallmark of Type 1 and Type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor Nkx6.1 in rat pancreatic islets induces -cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates -cell expansion has not been defined. Here we demonstrate that Nkx6.1 induces expression of the Nr4a1 and Nr4a3 orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated -cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in -cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphase-promoting complex, including Ube2c, resulting in degradation of the cell cycle inhibitor p21CIP1. These studies identify a new bipartite pathway for activation of -cell proliferation, suggesting several new targets for expansion of functional -cell mass.

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Tessem JS, Moss LG, Chao LC, Arlotto M, Lu D, Jensen MV, Stephens SB, Tontonoz P, Hohmeier HE, Newgard CB