NOD/ShiLtJ

Stock number: 001976
Product name: NOD
Strain synonyms: Non-obese Diabetic
Research areas: Developmental Biology Research, Diabetes and Obesity Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Neurobiology Research, Research Tools, Sensorineural Research

Description

The NOD/ShiLtJ strain (commonly called NOD) is a polygenic model for autoimmune type 1 diabetes. Diabetes in NOD mice is characterized by hyperglycemia and insulitis, a leukocytic infiltration of the pancreatic islets. Marked decreases in pancreatic insulin content occur in females at about 12 weeks of age and several weeks later in males. A 2022 phenotyping study found that 86% of females and 48% of males became diabetic by 30 weeks of age; median female incidence was 18 weeks. Immune phenotypes in the NOD background consist of defects in antigen presentation, T lymphocyte repertoire, NK cell function, macrophage cytokine production, wound healing, and C5 complement. These defects make the NOD background a common choice for immunodeficient mouse strains. Diabetes onset data is available.

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Detailed description

Diabetes in NOD/ShiLtJ mice is characterized by insulitis, a leukocytic infiltrate of the pancreatic islets. Marked decreases in pancreatic insulin content occur in females at about 12 weeks of age and several weeks later in males. Onset of diabetes is marked by moderate glycosuria and by a non-fasting plasma glucose higher than 250 mg/dl. Diabetic mice are hypoinsulinemic and hyperglucagonemic, indicating a selective destruction of pancreatic islet beta cells. Susceptibility to IDDM in NOD/ShiLtJ mice is polygenic, and environment, including housing conditions, health status, and diet, exerts a strong effect on penetrance. NOD/ShiLtJ females are more widely used than males because the onset of IDDM symptoms occurs earlier and with a higher incidence (90-100% by 30 weeks of age). NOD/ShiLtJ males develop IDDM at a frequency of between 40-60% by 30-40 weeks of age. Male mice are useful for certain applications, including pharmaceutical studies, "accelerated transfer" of IDDM, and some in vitro studies. The major component of diabetes susceptibility in NOD mice is the unique MHC haplotype (H2^g7 = K^d, Aa^d, Ab^g7, E^null, D^b). NOD mice also exhibit multiple aberrant immunophenotypes including defective antigen presenting cell immunoregulatory functions, defects in the regulation of the T lymphocyte repertoire, defective NK cell function, defective cytokine production from macrophages (Fan et al., 2004) and impaired wound healing. They also lack hemolytic complement, C5. NOD/ShiLtJ mice also are severely hearing-impaired. A variety of mutations causing immunodeficiencies, targeted mutations in cytokine genes, as well as transgenes affecting immune functions, have been backcrossed into the NOD/ShiLt inbred strain background.

Development

NOD inbred mice originated early on in the inbreeding of the Cataract Shionogi (CTS) strain. These mice were originally outbred Jcl:ICR mice. At F6, the progenitors of the future NOD/Shi mice were inbred on the basis of an elevated fasting blood glucose level in cataract-free mice. At F13, the NOD progenitors were separated from what is now the NON/Shi strain. High fasting blood glucose levels continued to be the basis for selection of the latter strain, while the NOD progenitors at F13 and later were selected on the basis of a normal fasting blood glucose level. In 1974, at F20, a female in the "normoglycemic" line spontaneously developed overt insulin-dependent diabetes mellitus with insulitis (IDDM). Selective breeding of the progeny of this diabetic female produced the nonobese diabetic (NOD) strain. Originally restricted to distribution in Japan, NOD substrains were distributed during the early 1980s to Australia and the United States. NOD and NON strains were imported from a colony in Kyoto, Japan by Dr. M. Hattori to the Joslin Diabetes Ceneter in Boston in 1984. Breeder pairs from this importation were sent from The Joslin Diabetes Center to Dr. E Leiter at The Jackson Laboratory, and are the source of the production strains NOD/ShiLtJ and NON/ShiLtJ.

Allele

Symbol: Il2^m1
Name: mutation 1
MGI accession ID: MGI:4352594
Generation method: Spontaneous
Marker symbol: Il2
Marker name: interleukin 2
Chromosome: 3
Strain of origin: multiple strains
Molecular note: This hypoactive polymorphism, found in MRL/MpJ, SJL/J, and NOD/ShiLtJ inbred strains, includes a smaller polyglutamine tract predicted to shorten the first alpha helix, which forms part of the IL2 receptor binding site.

Allele

Symbol: Hc⁰
Name: deficient
MGI accession ID: MGI:3027637
Generation method: Spontaneous
Marker symbol: Hc
Marker name: hemolytic complement
Chromosome: 2
Strain of origin: multiple strains
Molecular note: A 2 base "TA" deletion at positions 62 and 63 of an 83 base pair exon near the 5' end of the gene is found in the following mouse strains: A/HeJ, A/J, AKR/J, DBA/2J, I/LnJ, KK/HlJ, MOLF/EiJ, NZB/B1NJ, RF/J, ST/bJ SWR/J, B10.D2/oSnJ. The consequence of this deletion is the creation of a stop codon starting four bases after the deletion. A truncated product of 216 amino acids is predicted as a result although contradictory reports exist that a larger pro-C5 protein may be synthesized. Nevertheless, macrophages from mouse strains carrying this allele do not secrete complement 5.
General note:

This is an allele characteristic of various inbred mouse strains including the following: A/HeJ, A/J, AKR/J, DBA/2J, NZB/B1NJ, SWR/J, B10.D2/oSnJ

Hc was identified as a candidate gene for Abhr2 in a microarray analysis of lung mRNA from A/J, C3H/HeJ, and (A/J x C3H/HeJ)F1 x A/J backcross animals. Hc genotype shows statistically significant correlation to allergen-induced bronchial hyperresponsive phenotype. The A/J allele contains a 2 bp deletion resulting in deficient Hc mRNA and protein production and is associated with susceptibility to allergen-induced bronchial hyperresponsiveness. (J:108211)

Allele

Symbol: Cdh23^ahl
Name: age related hearing loss 1
MGI accession ID: MGI:3028349
Generation method: Spontaneous
Marker symbol: Cdh23
Marker name: cadherin 23 (otocadherin)
Chromosome: 10
Strain of origin: multiple strains
Molecular note: Genetic complementation tests have shown allelism between the mdfw (modifier of deaf waddler) locus and the ahl locus. Further analysis has shown this is caused by a G to A transition at coding nucleotide position 753 of Cdh23 (SNP rs257098870). This hypomorphic allele changes splice donor site G-GT to A-GT, causing frame skipping of exon 7. This is predicted to delete part of the 2nd and 3rd ectodomains and cause reduced message stability. Twenty-seven strains classified with ahl and carrying the 753A allele include: CD-1, RBF/DnJ, PL/J, AKR/J, RF/J, BALB/cBy, A/WySnJ, P/J, SENCARA/PtJ, DBA/1J, ALS/LtJ, C58/J, C57BLKS/J, 129P1/ReJ, C57BR/cd, SKH2/J, BUB/Bn, MA/MyJ, LP/J, 129X1/SvJ, NOR/LtJ, A/J, C57BL/6, NOD/LtJ, DBA/2J, ALR/LtJ, C57L/J. Strains classified with ahl that DO NOT carry this mutation include: 129S1/SvImJ, C3H/HeSnJ, I/LnJ, YBR/Ei, MRL/MpJ.

Allele

Symbol: mt-Tr^m1
Name: mutation 1
MGI accession ID: MGI:3831887
Generation method: Spontaneous
Marker symbol: mt-Tr
Marker name: mitochondrially encoded tRNA arginine
Chromosome: MT
Strain of origin: various
Molecular note: The adenine repeat in the D stem is polymorphic with 10 adenines in this allele.
General note: This polymorphism is present in A/J, NZB/B1NJ, ALS/Lt and NOD/ShiLtJ. A variant with 9 adenines is found in NOD/ShiLtDvs, ALR/Lt and SKH2/J.

Allele

Symbol: H2^g7
Name: g7 variant
MGI accession ID: MGI:3579321
Generation method: Not Applicable
Marker symbol: H2
Marker name: histocompatibility-2, MHC
Chromosome: 17
Strain of origin: Not Applicable
General note: The g7 variant has been observed in the following strains: DBR7, NON.NOD-H2^g7

Allele

Symbol: Gpr84^del
Name: deletion
MGI accession ID: MGI:5812913
Generation method: Spontaneous
Attributes: Null/Knockout
Marker symbol: Gpr84
Marker name: G protein-coupled receptor 84
Chromosome: 15
Strain of origin: multiple strains
Molecular note: This spontaneously arising frameshift deletion is located in exon 2 at position 103308576 bp (NCBI Build 37) and results in a premature stop codon. The mutation is predicted to result in a truncated protein lacking the transmembrane domains 4-7. The inbred strains BDP/J, DBA/1J, DBA/2J, I/LnJ, FVB/NJ, LG/J, MRL/MpJ, NODShi/LtJ, NOR/LtJ, P/J, PL/J, SKHIN/Sprd, SJL/J, SM/J are homozygous for the deletion. The allele is segregating in the outbred stocks ICR and CD-1.

Allele

Symbol: Del(3)1Lt
Name: deletion, Chr 3, Edward H Leiter 1
MGI accession ID: MGI:6120887
Generation method: Spontaneous
Attributes: Null/Knockout
Marker symbol: Del(3)1Lt
Marker name: deletion, Chr 3, Edward H Leiter 1
Chromosome: 3
Strain of origin: NOD/ShiLtJ
Molecular note: This spontaneous 111,169 bp deletion spans from Chr 3: 24,170,854 bp to 24,282,022 bp (GRCm38/mm10), and includes several QTL and the gene N-acetylated alpha-linked acidic dipeptidase-like 2

Allele

Symbol: Del(1)2Lt
Name: deletion, Chr 1, Edward H Leiter 2
MGI accession ID: MGI:6150933
Generation method: Spontaneous
Attributes: Not Applicable
Marker symbol: Del(1)2Lt
Marker name: deletion, Chr 1, Edward H Leiter 2
Chromosome: 1
Strain of origin: NOD/ShiLtJ
Molecular note: This spontaneous 25,703 bp deletion in Chromosome 1 spans from 39,088,990 bp to 39,114,692 bp (GRCm38).

Allele

Symbol: Del(3)3Lt
Name: deletion, Chr 3, Edward H Leiter 3
MGI accession ID: MGI:6150936
Generation method: Spontaneous
Attributes: Not Applicable
Marker symbol: Del(3)3Lt
Marker name: deletion, Chr 3, Edward H Leiter 3
Chromosome: 3
Strain of origin: NOD/ShiLtJ
Molecular note: This spontaneous 4,289 bp deletion in Chromosome 3 spans from 33,746,227 bp to 33,750,515 bp (GRCm38).

Allele

Symbol: Cox7a2l^l
Name: long
MGI accession ID: MGI:6276121
Generation method: Not Applicable
Attributes: Not Specified
Marker symbol: Cox7a2l
Marker name: cytochrome c oxidase subunit 7A2 like
Chromosome: 17
Strain of origin: multiple strains
Molecular note: This allele encodes the long isoform with 113 amino acids. It is found in 129S2/SvPasCrl, CBA/CaOlaHsd, Hsd:ICR, and NZB/OlaHsd.
General note: Querying the sequences of the Sanger Mouse Genomes Project reveals that the short allele with its 6 bp deletion exists in C57BL/6J, C57BL/10J, C57BL/6NJ, C58/J, BALB/cJ, C3H/HeH, 129S5/SvEvBrd, NZW/LacZ, and SEA/GnJ, but the long allele lacking the deletion exists in 129S1/SvImJ, A/J, AKR/J, BTBR T⁺ Itpr3^tf/J, BUB/BnJ, C3H/HeJ, C57BR/cdJ, C57L/J, CAST/EiJ, CBA/J, DBA/1J, DBA/2J, FVB/NJ, I/LnJ, KK/HiJ, LEWES/EiJ, LP/J, MOLF/EiJ, NOD/ShiLtJ, NZB/BlNJ, NZO/HlLtJ, PWK/PhJ, RF/J, SPRET/EiJ, ST/bJ, WSB/EiJ, ZALENDE/EiJ.