title: Unexpected functional consequences of xenogeneic transgene expression in beta-cells of NOD mice.
abstract: We describe unexpected alterations in the non-obese diabetic (NOD/Lt) mouse model of type 1 diabetes (T1D) following forced beta-cell expression of non-mammalian genes ligated to an insulin promoter sequence. These include the jellyfish green fluorescent protein (GFP), useful for beta-cell identification, and the bacteriophage P1 Cre recombinase, necessary for beta 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 beta 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. ehl@jax.org
authors.forename: E H
authors.initials: EH
authors.lastname: Leiter
authors.forename: P
authors.initials: P
authors.lastname: Reifsnyder
authors.forename: J
authors.initials: J
authors.lastname: Driver
authors.forename: S
authors.initials: S
authors.lastname: Kamdar
authors.forename: C
authors.initials: C
authors.lastname: Choisy-Rossi
authors.forename: D V
authors.initials: DV
authors.lastname: Serreze
authors.forename: M
authors.initials: M
authors.lastname: Hara
authors.forename: A
authors.initials: A
authors.lastname: Chervonsky
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000276:immunology*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic / Q000235:genetics / Q000276:immunology*; D010179:Pancreas / Q000473:pathology; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases