Pax6 and Cdx2/3 form a functional complex on the rat glucagon gene promoter G1‐element

Andersen, Frank G.; Heller, R. Scott; Petersen, Helle V.; Jensen, Jan; Madsen, Ole; Serup, Palle

doi:10.1016/s0014-5793(99)00145-3

Cited by 33 publications

(26 citation statements)

References 45 publications

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“…The paired-homeodomain transcription factor Pax6 is implicated in ␣ cell development shown by a reduction in glucagonproducing cells in Pax6 null mice (18,22), and Pax6 binds to a proximal element in the glucagon promoter and up-regulates glucagon gene transcription (23,24). An increase in Pax6 may increase glucagon gene expression.…”

Section: Resultsmentioning

confidence: 99%

Brn-4 Transcription Factor Expression Targeted to the Early Developing Mouse Pancreas Induces Ectopic Glucagon Gene Expression in Insulin-producing β Cells

Hussain

Miller²,

Habener

2002

Journal of Biological Chemistry

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The endocrine pancreas is comprised of ␤ and ␣ cells producing the glucostatic hormones insulin and glucagon, respectively, and arises during development by the differentiation of stem/progenitor cells in the foregut programmed by the ␤ cell lineage-specific homeodomain protein Idx-1. Brain-4 (Brn-4) is expressed in the pancreatic anlaga of the mouse foregut at e10 in the ␣ cells and transactivates glucagon gene expression. We expressed Brn-4 in pancreatic precursors or ␤ cell lineage in transgenic mice by placing it under either Idx-1 or insulin promoter (rat insulin II promoter) control, respectively. Idx-1 expression occurs at developmental day e8.5, and insulin expression occurs at e9.5, respectively. Misexpression of Brn-4 by the Idx-1 promoter results in ectopic expression of the proglucagon gene in insulin-expressing pancreatic ␤ cells, whereas misexpression by rat insulin II promoter did not. The early developmental expression of Brn-4 appears to be a dominant regulator of the glucagon expressing ␣ cell lineage, even in the context of the ␤ cell lineage.The mammalian pancreas develops by the differentiation of endodermal stem/progenitor cells in the foregut of the developing embryo (Refs. 1-3 and references therein). These progenitor cells differentiate into the exocrine acinar cells that produce digestive enzymes and the endocrine islets of Langerhans consisting of the four types of cells specialized for the synthesis of the hormones glucagon (␣ cells), insulin (␤ cells), somatostatin (␦ cells), and pancreatic polypeptide (PP cells). Islet cell-specific differentiation requires the actions of the basic loop helix transcription factors neurogenin-3, ␤2/NeuroD, and the homeodomain proteins Isl-1, Pax4, Pax6, Nkx2.2, Nkx6.6, and Idx-1 (see Refs. 1-4 for review). Idx-1 (Pdx-1/Stf-1/Ipf-1) is transiently expressed in all pancreatic cells as well as in the epithelial layer of the duodenal mucosa during early embryogenesis (5-8). During development, Idx-1 becomes progressively confined to the endocrine ␤ cells where it is critical for the transcriptional regulation of the insulin gene (6, 9). Idx-1 null mice (7), as well as a child homozygous for an inactivating mutation of the Idx-1 (Ipf-1) gene (10), result in a failure of the pancreas to develop (pancreatic agenesis).Brn-4 is a member of the class III family of pou-homeodomain proteins that are highly expressed in neural stem cells and regulate stem cell-specific genes, such as the intermediate filament protein nestin (11, 12). During early pancreas development, the expression of Brn-4 is specifically restricted to stem/progenitor cells that later differentiate into glucagon-producing ␣ cells (13). Brn-4 has not been detected in either differentiating or mature ␤ cells. Brn-4 also stimulates glucagon gene expression by interaction with the ␣ cell-specific G 1 promoter element within the glucagon gene (14).Here we describe that the developmental misexpression of Brn-4 under the control of the mouse Idx-1 promoter (MIP) 1 in mice results in the ectopic expres...

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Section: Resultsmentioning

confidence: 99%

Brn-4 Transcription Factor Expression Targeted to the Early Developing Mouse Pancreas Induces Ectopic Glucagon Gene Expression in Insulin-producing β Cells

Hussain

Miller²,

Habener

2002

Journal of Biological Chemistry

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“…Our results further suggest that these transcription factors may regulate GIP gene transcription through a protein interaction or complex since multiple specific shifted bands were observed. Pax6 is known to complex with Pdx1 for binding to the somatostatin promoter (2) and with Brn-4 and Cdx2 for binding to the proglucagon promoter (1,18). Pax6 also interacts with other transcription factors to induce gene expression during eye development (10).…”

Section: Discussionmentioning

confidence: 99%

Pax6 and Pdx1 are required for production of glucose-dependent insulinotropic polypeptide in proglucagon-expressing L cells

Fujita¹,

Chui²,

King³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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cose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that play important roles in maintaining glucose homeostasis and are being actively pursued as novel therapeutic agents for diabetes. GIP is produced by dispersed enteroendocrine cells and interestingly at times is coexpressed with GLP-1. We sought to determine the factors that selectively define GIP-vs. GLP-1-expressing cells. We performed comparative immunostaining of Pax6 and Pdx1 in GIP-and GLP-1-secreting cells. We investigated whether Pax6 and Pdx1 activate the human GIP promoter in control IEC-6 cells and GIP-expressing STC-1 cells. EMSA was performed to assess the binding of these transcription factors to the GIP promoter. Pax6 and Pdx1 consistently colocalized in GIP-immunoreactive cells. Cells that coexpress GIP and GLP-1 were Pax6 and Pdx1 positive, whereas cells expressing only GLP-1 were Pax6 positive but did not express Pdx1. GIP promoter activity was enhanced in IEC-6 cells by exogenous Pax6 or Pdx1 and diminished in STC-1 cells by inhibition of endogenous Pax6 or Pdx1 by dominantnegative forms. Promoter truncation analysis revealed a major loss of promoter activity when the sequence between Ϫ184 to Ϫ145 bp was deleted. EMSA studies indicated that Pax6 and Pdx1 bind to this proximal sequence of the human GIP promoter. Our findings indicate that concomitant expression of Pax6 and Pdx1 is important for GIP expression. Our results also suggest that the presence of Pdx1 defines whether GLP-1-expressing gastrointestinal L cells also coexpress GIP. transcriptional regulation; gut; K cell; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP, also known as gastric inhibitory polypeptide) and glucagon-like peptide-1 (GLP-1) are gastrointestinal hormones with pleiotropic

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“…Candidate genes are the homeobox genes flanking Pdx1 in the "Parahox cluster", Gsh1 and Cdx2. Both genes may be expressed in the developing pancreas and mature islets (Rosanas-Urgell et al 2005), and Cdx2 can transcriptionally activate Glucagon in pancreatic cell lines (Andersen et al 1999). It is also possible that deletion of Area I-II-III eliminates a repressor element resulting in ectopic expression of Pdx1; however, no ectopic expression was observed in any tissues at any of the stages examined.…”

Section: ⌬I-ii-iii/+mentioning

confidence: 99%

Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation

Fujitani¹,

Fujitani²,

Boyer³

et al. 2006

Genes Dev.

146

127

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Pax6 and Cdx2/3 form a functional complex on the rat glucagon gene promoter G1‐element

Cited by 33 publications

References 45 publications

Brn-4 Transcription Factor Expression Targeted to the Early Developing Mouse Pancreas Induces Ectopic Glucagon Gene Expression in Insulin-producing β Cells

Brn-4 Transcription Factor Expression Targeted to the Early Developing Mouse Pancreas Induces Ectopic Glucagon Gene Expression in Insulin-producing β Cells

Pax6 and Pdx1 are required for production of glucose-dependent insulinotropic polypeptide in proglucagon-expressing L cells

Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation

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