Islet-1 is essential for pancreatic β-cell function
- Benjamin N. Ediger1,5,
- Aiping Du1⇑,
- Jingxuan Liu1,
- Chad S. Hunter3,
- Erik R. Walp1,
- Jonathan Schug4,
- Klaus H. Kaestner4,
- Roland Stein3,
- Doris A. Stoffers5,*⇑ and
- Catherine Lee May*,1,2
- 1Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia
- 2Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- 3Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
- 4Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- 5Department of Medicine and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Corresponding Authors: Catherine Lee May, Email: , Doris A. Stoffers, Email:
* These authors contributed equally.
Isl-1 is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal β-cell by performing physiological and morphometric analyses of a tamoxifen-inducible, β-cell-specific Isl-1 loss of function mouse: Isl-1L/L; Pdx1-CreERTm. Ablating Isl-1 in postnatal β-cells reduced glucose tolerance without significantly reducing β-cell mass or increasing β-cell apoptosis. Rather, islets from Isl-1L/L; Pdx1-CreERTm mice showed impaired insulin secretion. To identify direct targets of Isl-1, we integrated high-throughput gene expression and Isl-1 chromatin occupancy using islets from Isl-1L/L; Pdx1-CreERTm mice and βTC3 insulinoma cells, respectively. Ablating Isl-1 significantly affected the β-cell transcriptome, including known targets Insulin and MafA as well as novel targets Pdx1 and Slc2a2. Using ChIP-Seq and luciferase reporter assays we found that Isl-1 directly occupies functional regulatory elements of Pdx1 and Slc2a2. Thus, Isl-1 is essential for postnatal β-cell function, directly regulates Pdx1 and Slc2a2, and has a mature β-cell cistrome distinct from that of pancreatic endocrine progenitors.
- Received January 17, 2014.
- Accepted July 10, 2014.
- © 2014 by the American Diabetes Association.
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