Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice
Ainhoa Iglesias, … , Francisco X. Real, Ana M. Zubiaga
Ainhoa Iglesias, … , Francisco X. Real, Ana M. Zubiaga
Published May 15, 2004
Citation Information: J Clin Invest. 2004;113(10):1398-1407. https://doi.org/10.1172/JCI18879.
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Article Metabolism

Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice

Abstract

E2F transcription factors are thought to be key regulators of cell growth control. Here we use mutant mouse strains to investigate the function of E2F1 and E2F2 in vivo. E2F1/E2F2 compound-mutant mice develop nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia, a reduction in the number and size of acini and islets, and their replacement by ductal structures and adipose tissue. Mutant pancreatic cells exhibit increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2F1/E2F2 compound-mutant pancreas, suggesting that their expression is repressed by E2F1/E2F2 activities and that the inappropriate cell cycle found in the mutant pancreas is likely the result of the deregulated expression of these genes. Interestingly, the expression of ductal cell and adipocyte differentiation marker genes was also upregulated, whereas expression of pancreatic cell marker genes were downregulated. These results suggest that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.

Authors

Ainhoa Iglesias, Matilde Murga, Usua Laresgoiti, Anouchka Skoudy, Irantzu Bernales, Asier Fullaondo, Bernardino Moreno, José Lloreta, Seth J. Field, Francisco X. Real, Ana M. Zubiaga

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Figure 2

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Pancreatic histopathology of E2F1/E2F2 double homozygotes. Pancreas sect...
Pancreatic histopathology of E2F1/E2F2 double homozygotes. Pancreas sections obtained from E2F-deficient and WT animals stained with H&E. (A and B) Representative pancreas section of 7-day-old (A) and 2-month-old (B) WT male mice. Magnification, ∞600. (C and D) Representative pancreas section of 2-month-old (C) and 6-month-old (D) E2F1-deficient male mice showing aberrantly large nuclei (marked with arrowheads). Magnification, ∞600. (E_G) Representative pancreas section of 7-day-old (E) and 2-month-old (F and G) DKO male mice. (E and F) Magnification, ∞600. (G) Magnification, ∞400. The acini and islets (marked with an asterisk) in the DKO pancreas are abnormal and have lost their typical tubular organization, which has been replaced by ductal structures. Note the dysplasic changes in acinar cells, characterized by hypertrophy and karyomegaly. (H) Representative pancreas section of a 2-month-old E2F2-deficient male mouse. Magnification, ∞600. The morphology of the pancreas in female E2F-deficient mice was essentially the same as the morphology of the pancreas in male counterparts (data not shown). The sections shown are representative examples from histology for six WT (n = 3 male, n = 3 female), 15 DKO (n = 8 male, n = 7 female), six E2F1_/_ (n = 3 male, n = 3 female), and six E2F2_/_ (n = 3 male, n = 3 female) mice.