Inducible and Reversible β-Cell Autoimmunity and Hyperplasia in Transgenic Mice Expressing a Conditional Oncogene
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Figures
- FIG. 1.
Tag expression in newborn RIP7-rtTA × tet-Tag double-transgenic mice. Sections of the pancreas from double-transgenic newborn mice born to females treated with dox from early pregnancy (A) or untreated (B) were immunostained for Tag. Magnification is 375×.
- FIG. 2.
Islet β-cell proliferation is dependent on Tag expression. Mice were treated with dox starting from embryonic development until 5 weeks of age (A and B) or until 4 weeks of age, followed by 1 week in the absence of dox (C and D). Pancreas sections were immunostained for Tag (A and C) and BrdU (B and D). Magnification is 113×.
- FIG. 3.
Insulitis induced by late onset of Tag expression and reversed by shut-off of Tag expression. Double-transgenic RIP7-rtTA × tet-Tag mice were treated with dox starting at 3 weeks of age. HE staining of pancreas sections at 8 weeks of age revealed insulitis in the islets (A). The area of cell infiltration is devoid of insulin immunostaining in an adjacent section (B). Insulitis did not delay the formation of insulinomas by 12 weeks of age (C and D, HE staining). In mice in which dox treatment was terminated at 8 weeks of age, no insulitis was visible in the majority of the islets by 12 weeks (E and F, HE staining). Arrows mark areas of insulitis. Broken lines mark tumor boundaries. Magnification is 49× (A and B), 16× (C and E), and 139× (D and F).
- FIG. 4.
Reversibility of insulitis after shut-off of Tag expression. Double-transgenic RIP7-rtTA × tet-Tag mice were treated with dox between 3 and 8 weeks of age. Pancreas histology was analyzed at the indicated time points after dox removal. The number of islets with insulitis is expressed as a percent of the combined total islet number in 3–4 mice analyzed at each time point (except for the 6-week time point, at which time 10 mice were scored) .
- FIG. 5.
Islet cell apoptosis in RIP7-rtTA × tet-Tag mice during Tag expression and after shutoff of Tag expression. Double-transgenic mice were treated with dox between 3 and 8 weeks of age. The pancreas was removed at the termination of dox treatment (A and B) or after 3 (C and D) or 4 (E and F) additional weeks in the absence of dox. Pancreas sections were analyzed by HE staining (A, C, and E) and by a TUNEL assay for apoptotic cells in adjacent sections (B, D, and F). Arrows in A and B mark areas of insulitis. Magnification is 49× (A and B), 65× (C and D), and 194× (E and F)
- FIG. 6.
Decrease in islet cell apoptosis after shut-off of Tag expression. Mice treated with dox between 3 and 8 weeks of age were analyzed at the indicated time points after dox removal. Pancreas sections were stained for apoptotic cells by a TUNEL assay. Labeled nuclei were counted in pancreas sections of 3–4 mice for each time point (except for the 6-week time point, at which 10 mice were scored). Ten average-size islets similar in size to those shown in Fig. 5D, each containing several hundred cells, were scored in each pancreas. Values are expressed as a percentage of the total cell number in the islets scored and represent the means ± SE.
- FIG. 7.
Persistence of hyperplastic islets lacking proliferating and apoptotic cells in some RIP7-rtTA × tet-Tag mice. Mice treated with dox between 3 and 8 weeks of age were analyzed at 16 weeks of age. Pancreas sections were stained with HE (A), Tag antibody (B), and BrdU antibody (C) and were analyzed in a TUNEL assay (D). Magnification is 66×.
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