Unexpected functional consequences of xenogeneic transgene expression in β-cells of NOD mice

We describe unexpected alterations in the non-obese diabetic (NOD/Lt) mouse model of type 1 diabetes (T1D) following forced β-cell expression of non-mammalian genes ligated to an insulin promoter sequence. These include the jellyfish green fluorescent protein (GFP), useful for β-cell identification,...

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Bibliographic Details
Published in:Diabetes, obesity & metabolism obesity & metabolism, 2007-11, Vol.9 (s2), p.14-22
Main Authors: Leiter, E.H, Reifsnyder, P, Driver, J, Kamdar, S, Choisy-Rossi, C, Serreze, D.V, Hara, M, Chervonsky, A
Format: Article
Language:English
Subjects:
Animals
Cre recombinase
diabetes
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - immunology
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - immunology
Female
Gene Expression
green fluorescent protein
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Insulin-Secreting Cells - immunology
Integrases - genetics
Integrases - metabolism
Male
Mice
Mice, Inbred NOD
Mice, Transgenic - genetics
Mice, Transgenic - immunology
NOD mice
Pancreas - pathology
Transgenes
β cells
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Summary:We describe unexpected alterations in the non-obese diabetic (NOD/Lt) mouse model of type 1 diabetes (T1D) following forced β-cell expression of non-mammalian genes ligated to an insulin promoter sequence. These include the jellyfish green fluorescent protein (GFP), useful for β-cell identification, and the bacteriophage P1 Cre recombinase, necessary for β cell-specific ablation of a gene using a Cre-loxP system. Homozygous expression of GFP, driven by the mouse insulin 1 gene promoter (MIP-GFP) in a single transgenic line of NOD mice, produced T1D in postnatal mice that was not associated with insulitis, but rather β cell-depleted islets. Hemizygous transgene expression suppressed spontaneous autoimmune T1D in females, and produced a male glucose intolerance syndrome associated with age-dependent declines in plasma insulin content. Among lines of transgenic NOD/Lt mice expressing Cre recombinase driven by the rat insulin 2 promoter (RIP-Cre), high, non-mosaic expression correlated with suppressed T1D development. These findings emphasize the need for careful characterization of genetically manipulated NOD mouse stocks to insure that model characteristics have not been compromised.
ISSN:1462-8902
1463-1326
DOI:10.1111/j.1463-1326.2007.00770.x