Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription.
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, SEYNeu, represses proglucagon gene transcription in enteroendocrine cells. Mice homozygous for the SEYNeu 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.
Hill
M E
ME
Department of Medicine, The Banting and Best Diabetes Centre, Toronto General Hospital, Ontario, Canada.
Asa
S L
SL
Drucker
D J
DJ
D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000378:metabolism*; D005136:Eye Proteins; D005260:Female; D005786:Gene Expression Regulation; D005934:Glucagon / Q000235:genetics* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D018398:Homeodomain Proteins; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000737:chemistry; D007515:Islets of Langerhans / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D052336:Proglucagon; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D014018:Tissue Distribution; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D005136:Eye Proteins; D053767:Glucagon-Like Peptide 2; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008156:Luciferases