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Title: Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors      
keywords:
Transcriptome or Gene expression
ID:
PRJNA238469
description:
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 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 Nr4a1 and Nr4a3 orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in β-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 β-cell proliferation, suggesting several new targets for expansion of functional β-cell mass. Overall design: We set up a microarray using primary rat islets that were left untreated or transduced with adenoviruses overexpressing βgal or Nkx6.1 for 48 h.
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA238469
authentication:
none
authorization:
none
ID:
pmid:24706823
name:
Rattus norvegicus
ncbiID:
ncbitax:10116
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • U01 DK089538/DK/NIDDK NIH HHS/United States

  • Howard Hughes Medical Institute/United States

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