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Essential Requirement for Pax6 in Control of Enteroendocrine Proglucagon Gene Transcription

Department of Medicine (M.F.H., D.J.D.) The Banting and Best Diabetes Centre Toronto General Hospital Toronto, Ontario M5G 2C4, Canada
Department of Pathology (S.L.A.) The Mount Sinai Hospital University of Toronto Toronto, Ontario M5G 2C4, Canada

The primary function of islet A cells is the synthesis and secretion of glucagon, an essential hormonal regulator of glucose homeostasis. The proglucagon gene is also expressed in enteroendocrine L cells of the intestinal epithelium, which produce glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), regulators of insulin secretion and intestinal growth, respectively. We show here that Pax6, a critical determinant of islet cell development and proglucagon gene expression in islet A cells, is also essential for glucagon gene transcription in the small and large intestine. Pax6 is expressed in enteroendocrine cells, binds to the G1 and G3 elements in the proglucagon promoter, and activates proglucagon gene transcription. The dominant negative Pax6 allele, SEY^Neu, represses proglucagon gene transcription in enteroendocrine cells. Mice homozygous for the SEY^Neu mutation exhibit markedly reduced levels of proglucagon mRNA transcripts in the small and large intestine, and GLP-1 or GLP-2-immunopositive enteroendocrine cells were not detected in the intestinal mucosa. These findings implicate an essential role for Pax6 in the development and function of glucagon-producing cells in both pancreatic and intestinal endodermal lineages.

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