Islet-1 is essential for pancreatic β-cell function

  1. Catherine Lee May*,1,2
  1. 1Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia
  2. 2Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
  4. 4Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  5. 5Department of Medicine and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  1. Corresponding Authors: Catherine Lee May, Email: catheril{at}mail.med.upenn.edu, Doris A. Stoffers, Email: stoffers{at}mail.med.upenn.edu
  1. * These authors contributed equally.

Abstract

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.

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  1. Diabetes
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