title: The effect of neurogenin3 deficiency on pancreatic gene expression in embryonic mice.
abstract: To understand the molecular mechanisms regulating pancreatic endocrine development and function, pancreatic gene expression was compared between Ngn3-deficient mice and littermate controls on embryonic days 13 and 15. Microarray analysis identified 504 genes with significant differences in expression. Fifty-two of these showed at least twofold reduction in Ngn3 knockouts compared to controls. Many of them were previously described to be involved in endocrine development and function. Among the genes not previously characterized were Rhomboid veinlet-like 4, genes involved in tetrahydrobiopterin biosynthesis and the Iroquois-type homeobox gene Irx1, the latter was selected for further investigation. In situ hybridisation demonstrated that two Iroquois genes, Irx1 and Irx2, were expressed in pancreatic endoderm of wild-type, but not Ngn3 mutant embryos. Furthermore, ectopic Ngn3 induced prominent Irx2 expression in chicken endoderm. Co-labelling established that Irx1 and Irx2 mRNA is located to glucagon-, but not insulin- or somatostatin-producing cells in mice and chicken. These data suggest that Irx1 and Irx2 serve an evolutionary conserved role in the regulation of alpha-cell-specific gene expression.
authors.affiliation: Department of Molecular Genetics, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Petri
authors.forename: Jonas
authors.initials: J
authors.lastname: Ahnfelt-Rønne
authors.forename: Klaus Stensgaard
authors.initials: KS
authors.lastname: Frederiksen
authors.forename: David George
authors.initials: DG
authors.lastname: Edwards
authors.forename: Dennis
authors.initials: D
authors.lastname: Madsen
authors.forename: Palle
authors.initials: P
authors.lastname: Serup
authors.forename: Jan
authors.initials: J
authors.lastname: Fleckner
authors.forename: R Scott
authors.initials: RS
authors.lastname: Heller
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology*; D002642:Chick Embryo; D016000:Cluster Analysis; D004707:Endoderm / Q000378:metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D050416:Glucagon-Secreting Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C501592:Irx1 protein, mouse; C501596:Irx2 protein, mouse; C407737:Neurog3 protein, mouse