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


ABSTRACT: Loss of functional beta-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 beta-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates beta-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 beta-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in beta-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 beta-cell proliferation, suggesting several new targets for expansion of functional beta-cell mass. We set up a microarray using primary rat islets that were left untreated or transduced with adenoviruses overexpressing betagal or Nkx6.1 for 48 h.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Larry Moss 

PROVIDER: E-GEOD-55077 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Tessem Jeffery S JS   Moss Larry G LG   Chao Lily C LC   Arlotto Michelle M   Lu Danhong D   Jensen Mette V MV   Stephens Samuel B SB   Tontonoz Peter P   Hohmeier Hans E HE   Newgard Christopher B CB  

Proceedings of the National Academy of Sciences of the United States of America 20140324 14


Loss of functional β-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 NK6 homeobox 1 (Nkx6.1) in rat pancreatic islets induces β-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates β-cell expansion has not been defined. Here, we demonstrate that Nkx6.1 induces expression of the nuclear receptor  ...[more]

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