The effect of neurogenin3 deficiency on pancreatic gene expression in embryonic mice.
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.
Petri
Andreas
A
Department of Molecular Genetics, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark.
Ahnfelt-Rønne
Jonas
J
Frederiksen
Klaus Stensgaard
KS
Edwards
David George
DG
Madsen
Dennis
D
Serup
Palle
P
Fleckner
Jan
J
Heller
R Scott
RS
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
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