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. 1998 Jun 15;12(12):1763-8.
doi: 10.1101/gad.12.12.1763.

beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes

U Ahlgren  1 , J Jonsson, L Jonsson, K Simu, H Edlund
Affiliations

beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes

U Ahlgren et al. Genes Dev. .

Abstract

To study the late beta-cell-specific function of the homeodomain protein IPF1/PDX1 we have generated mice in which the Ipf1/Pdx1 gene has been disrupted specifically in beta cells. These mice develop diabetes with age, and we show that IPF1/PDX1 is required for maintaining the beta cell identity by positively regulating insulin and islet amyloid polypeptide expression and by repressing glucagon expression. We also provide evidence that IPF1/PDX1 regulates the expression of Glut2 in a dosage-dependent manner suggesting that lowered IPF1/PDX1 activity may contribute to the development of type II diabetes by causing impaired expression of both Glut2 and insulin.

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Figures

Figure 1
Figure 1
Cre–loxP-mediated targeting of the Ipf1/Pdx1 gene. (A) Schematic representation of targeting construct, genomic DNA, and the expected product of Cre/loxP recombination. The PCR primers used for genotyping and the probes used for confirmation of correct recombination events are shown. (B) RT–PCR analysis using Cre- and rpS17 control primers on total RNA prepared from the alimentary tract of E10.5, E12.5, and E14.5 Rip1/Ipf1▴ and E14.5 Ipf1+/+ (ctrl) embryos. Pancreatic sections from neonatal (C), 3 (D)-, and 5 (E)-week-old prediabetic Rip1/Ipf1▴ mice stained with anti-Ins and anti-IPF1 antibodies. (F–O) β-Cell-specific loss of Ipf1/Pdx1 affects the β-cell phenotype. Confocal images showing Ipf1+/+ (F,H,J,L,N) and diabetic Rip1/Ipf1▴ (G,I,K,M,O) islets from 18-week-old mice. See text for details. (C–O) Bar, 10 μm.
Figure 2
Figure 2
Rip1/Ipf1▴ mice show abnormal islet composition. (A) The distribution of insulin (Ins+)-, IAPP (IAPP+)-, or glucagon (Glu+)-expressing cells per total number of islet cells in wild-type and Rip1/Ipf1 mice. (B) Ratio of Ins+ to IAPP+ cells in islets from wild-type and Rip1/Ipf1 mice. (Open area) Ins+ only; (solid area) IAPP+ only; (shaded area) Ins+ and IAPP+ coexpressed. (C) Ratio of Ins+ to Glu+ cells in islets from wild-type and Rip1/Ipf1 mice. (Open area) Ins+ only; (solid area) Glu+ only; (shaded area) Ins+ and Glu+ coexpressed. (A–C) n = 600–1050 cells.
Figure 3
Figure 3
Glut2 expression is dependent on high levels of IPF1/PDX1 expression. Analysis of Glut2 expression in correlation to IPF1 expression by immunohistochemistry on pancreas from 18-week diabetic Rip1/Ipf1▴ (A,E,I), 11-week ND Rip1/Ipf1▴ (B,F,J), 18-week Ipf1+/+ (C,G,K), and 18-week Ipf1+/− mice (D,H,L) (Jonsson et al. 1994). Images are representative of at least 10 different islets. Bar, 20 μm.
Figure 4
Figure 4
Heterozygosity for the Ipf1/Pdx1 null mutation results in impaired glucose tolerance. Glucose challenge of 18-week-old Ipf1+/+ (▪) and Ipf1+/− (♦) (Jonsson et al. 1994) mice. Blood glucose levels are shown at indicated time points after IP administration of glucose. Results are mean ± s.e.m. of eight animals in each group.
See this image and copyright information in PMC

References

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