Islet-1 is required for the maturation, proliferation and survival of the endocrine pancreas
- Aiping Du1,
- Chad S. Hunter5,
- Johanna Murray1,
- Daniel Noble1,
- Chen-Leng Cai6,
- Sylvia M. Evans4,
- Roland Stein5 and
- Catherine Lee May (catheril{at}mail.med.upenn.edu)1,2,3
- 1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia
- 2Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine
- 3Institute for Diabetes, Obesity and Metabolism, Philadelphia, Pennsylvania 19104, USA
- 4Institute of Molecular Medicine, Department of Medicine, UC San Diego, La Jolla, CA 92093, USA
- 5Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
- 6Department of Developmental and Regenerative Biology, Center for Molecular Cardiology & Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA
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 (E)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 severely 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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- Received July 21, 2008.
- Accepted May 26, 2009.
- Copyright © American Diabetes Association
