2022
DOI: 10.1210/endocr/bqac144
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β-Cell Cre Expression and Reduced Ins1 Gene Dosage Protect Mice From Type 1 Diabetes

Abstract: A central goal of physiological research is the understanding of cell-specific roles of disease-associated genes. Cre-mediated recombineering is the tool of choice for cell type-specific analysis of gene function in pre-clinical models. In the type 1 diabetes research field, multiple lines of NOD mice have been engineered to express Cre recombinase in pancreatic β-cells using insulin promoter fragments, but tissue promiscuity remains a concern. Constitutive Ins1tm1.1(cre)Thor (Ins1Cre) mice on the C57/bl6-J ba… Show more

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Cited by 5 publications
(4 citation statements)
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“…To overcome the limitation associated with replacing a single Ins1 gene with Cre recombinase in our NOD. Ins1 Cre ; Scn9a flox mice 42 , we instead used the pancreas-biased AAV8 virus serotype and a highly specific Ins1 -promoter to deliver Cre specifically to β-cells for deletion of Scn9a at 6-7 weeks (Fig. 8A).…”
Section: Resultsmentioning
confidence: 99%
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“…To overcome the limitation associated with replacing a single Ins1 gene with Cre recombinase in our NOD. Ins1 Cre ; Scn9a flox mice 42 , we instead used the pancreas-biased AAV8 virus serotype and a highly specific Ins1 -promoter to deliver Cre specifically to β-cells for deletion of Scn9a at 6-7 weeks (Fig. 8A).…”
Section: Resultsmentioning
confidence: 99%
“…These results differ from the observations made in our Ins1 Cre mice. These inconsistencies are believed to be mainly attributed to the removal of a single Ins1 allele and the associated changes in insulin dosage 42,76 While the AAV8- Ins1 Cre mouse model addresses the limitations associated with insulin dosage, it still relies on Cre to create gene conditional knockouts and as a result is restricted by the protective effects of Cre expression in NOD, beyond losing one Ins1 allele 42 . However, we observed that diabetes incidence rates in our WT AAV8- Ins1 Cre control were comparable to wildtype controls with no AAV8- Ins1 Cre and previously reported in WT NOD mice 77,78 , regardless of housing facility differences.…”
Section: Discussionmentioning
confidence: 99%
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“…Enforced early proliferation of young beta cells in NOD mice by liver insulin receptor knockout (LIRKO) before immune cell infiltration led to profound changes in antigen presentation concomitant with a diminution of autoreactive T cell activity [ 55 ]. NOD mice harbouring Ins1-Cre or a reduced dose of insulin genes show a lower diabetes penetrance but no major changes in autoantibodies or insulitis [ 56 ], and swapping the mouse Ins1 gene for the human INS gene also has a protective effect in NOD mice [ 57 ]. Given the role of insulin as a major autoantigen in type 1 diabetes, the findings from these latter studies are also consistent with altered/reduced presentation of insulin antigens, leading to slower autoimmunity progression and lower type 1 diabetes penetrance in NOD mice.…”
Section: How Does Islet Autoimmunity Progress? a Role For Antigen Pre...mentioning
confidence: 99%