Islet α-, β-, and δ-Cell Development Is Controlled by the Ldb1 Coregulator, Acting Primarily With the Islet-1 Transcription Factor
- Chad S. Hunter1,
- Shilpy Dixit1,
- Tsadok Cohen2,
- Benjamin Ediger3,
- Crystal Wilcox3,
- Mark Ferreira3,
- Heiner Westphal2,
- Roland Stein1⇓ and
- Catherine Lee May3⇓
- 1Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville Tennessee
- 2Section on Mammalian Molecular Genetics, Program in Genomics of Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
- 3Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- Corresponding authors: Roland Stein, , and Catherine Lee May, .
Ldb1 and Ldb2 are coregulators that mediate Lin11-Isl1-Mec3 (LIM)–homeodomain (HD) and LIM-only transcription factor–driven gene regulation. Although both Ldb1 and Ldb2 mRNA were produced in the developing and adult pancreas, immunohistochemical analysis illustrated a broad Ldb1 protein expression pattern during early pancreatogenesis, which subsequently became enriched in islet and ductal cells perinatally. The islet-enriched pattern of Ldb1 was similar to pan-endocrine cell–expressed Islet-1 (Isl1), which was demonstrated in this study to be the primary LIM-HD transcription factor in developing and adult islet cells. Endocrine cell–specific removal of Ldb1 during mouse development resulted in a severe reduction of hormone+ cell numbers (i.e., α, β, and δ) and overt postnatal hyperglycemia, reminiscent of the phenotype described for the Isl1 conditional mutant. In contrast, neither endocrine cell development nor function was affected in the pancreas of Ldb2−/− mice. Gene expression and chromatin immunoprecipitation (ChIP) analyses demonstrated that many important Isl1-activated genes were coregulated by Ldb1, including MafA, Arx, insulin, and Glp1r. However, some genes (i.e., Hb9 and Glut2) only appeared to be impacted by Ldb1 during development. These findings establish Ldb1 as a critical transcriptional coregulator during islet α-, β-, and δ-cell development through Isl1-dependent and potentially Isl1-independent control.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0952/-/DC1.
- Received July 17, 2012.
- Accepted September 11, 2012.
- © 2013 by the American Diabetes Association.
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