Islet-1 is Required for the Maturation, Proliferation, and Survival of the Endocrine Pancreas
- Aiping Du1,
- Chad S. Hunter2,
- Johanna Murray1,
- Daniel Noble1,
- Chen-Leng Cai3,
- Sylvia M. Evans4,
- Roland Stein2 and
- Catherine Lee May1,5,6
- 1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
- 2Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee;
- 3Department of Developmental and Regenerative Biology, Center for Molecular Cardiology & Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York;
- 4Institute of Molecular Medicine, Department of Medicine, University of California San Diego, La Jolla, California;
- 5Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
- 6Institute for Diabetes, Obesity and Metabolism, Philadelphia, Pennsylvania.
- Corresponding author: Catherine Lee May, catheril{at}mail.med.upenn.edu.
Abstract
OBJECTIVE The generation of mature cell types during pancreatic development depends on the expression of many regulatory and signaling proteins. In this study, we tested the hypothesis that the transcriptional regulator Islet-1 (Isl-1), whose expression is first detected in the mesenchyme and epithelium of the developing pancreas and is later restricted to mature islet cells, is involved in the terminal differentiation of islet cells and maintenance of islet mass.
RESEARCH DESIGN AND METHODS To investigate the role of Isl-1 in the pancreatic epithelium during the secondary transition, Isl-1 was conditionally and specifically deleted from embryonic day 13.5 onward using Cre/LoxP technology.
RESULTS Isl-1–deficient endocrine precursors failed to mature into functional islet cells. The postnatal expansion of endocrine cell mass was impaired, and consequently Isl-1 deficient mice were diabetic. In addition, MafA, a potent regulator of the Insulin gene and β-cell function, was identified as a direct transcriptional target of Isl-1.
CONCLUSIONS These results demonstrate the requirement for Isl-1 in the maturation, proliferation, and survival of the second wave of hormone-producing islet cells.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received July 21, 2008.
- Accepted May 26, 2009.
- © 2009 by the American Diabetes Association.
