Islet α-, β-, and δ-cell development is controlled by the Ldb1 coregulator, acting primarily with the islet-1 transcription factor.

Hunter CS, Dixit S, Cohen T, Ediger B, Wilcox C, Ferreira M, Westphal H, Stein R, May CL
Diabetes. 2013 62 (3): 875-86

PMID: 23193182 · PMCID: PMC3581213 · DOI:10.2337/db12-0952

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.

MeSH Terms (21)

Animals Cell Nucleus DNA-Binding Proteins Female Gene Expression Regulation Glucagon-Secreting Cells Insulin-Secreting Cells Islets of Langerhans LIM-Homeodomain Proteins LIM Domain Proteins Male Mice Mice, Knockout Mice, Mutant Strains Mice, Transgenic Organogenesis Organ Specificity Protein Isoforms RNA, Messenger Somatostatin-Secreting Cells Transcription Factors

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