NOD.Cg-Rag1^tm1Mom Ins2^Akita Il2rg^tm1Wjl/SzJ

Stock number: 014568
Product name: NRG Akita
Research areas: Cancer Research, Cell Biology Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools

Description

These NRG-Akita mutant mice are immunodeficient and spontaneously develop hyperglycemia. The strain may be useful as a diabetic host for human islet cells.

Detailed description

NRG-Akita mice, which are homozygous for the Rag1^tm1Mom and the Il2rg^tm1Wjl alleles (males are hemizygous for the X-linked Il2rg^tm1Wjl allele) and heterozygous for the Ins2^Akita allele, develop spontaneous hyperglycermia. No mature T, B or NK cells are detected in flow cytometric analysis of splenocytes from NRG-Akita mutant mice. Granulocyte and macrophage populations are similar to those seen in NRG mice (Stock No. 7799). NRG-Akita mice develop hyperglycemia between 3 and 5 weeks of age. Histological examination at 3 weeks of age reveals normal pancreas morphology, and routine insulin and glucagon staining. By approximately 32 weeks of age, NRG-Akita mice display disorganized, condensed pancreatic islet architecture, with loss of insulin-positive cells. Euglycemia is restored by subrenal transplantation of mouse or human islets or intrapancreatic transplantation of dissociated mouse islet cells. NRG-Akita mice engrafted with human hematopoietic stem cells (HSC) develop humanized immune systems. Approximately 60% of the human HSC engrafted NRG-Akita mice reject human islet allografts.

Development

To generate this strain NOD.Cg-Rag1^tm1Mom Ins2^Akita Prf1^tm1Sdz/SzJ (Stock No. 008659) mice were crossed with NOD.Cg-Rag1^tm1Mom Il2rg^tm1Wjl/SzJ (Stock No. 007799) mice. The Prf1^tm1Sdz allele was bred out, and the mice were made homozygous for the Rag1^tm1Mom and the Il2rg^tm1Wjl alleles and heterozygous for the Ins2^Akita allele with subsequent crosses.

Allele

Symbol: Rag1^tm1Mom
Name: targeted mutation 1, Peter Mombaerts
MGI accession ID: MGI:1857241
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Rag1
Marker name: recombination activating gene 1
Chromosome: 2
Strain of origin: 129S7/SvEvBrd-Hprt⁺
Site of expression: expression is seen in bone marrow derived cell lines.
Molecular note: A 1356 bp genomic fragment of the Rag1 gene, encoding the nuclear localization signal and the zinc-finger motif, was replaced by a neomycin cassette. A mutant transcript expressed from this allele was detected by Northern blot in bone marrow derived cell lines from homozygous mice.

Allele

Symbol: Ins2^Akita
Name: Akita
MGI accession ID: MGI:1857572
Generation method: Spontaneous
Marker symbol: Ins2
Marker name: insulin II
Chromosome: 7
Strain of origin: C57BL/6NSlc
Molecular note: In the mutant allele a transition from G-to-A at coding nucleotide 287 disrupts an Fnu4HI site in exon 3. This mutation changed the seventh amino acid in the A chain of mature insulin, Cys96 (TGC), to Tyr (TAC) (p.C96Y). The authors predict that the transition would disrupt a disulfide bond between the A and the B chains and would likely induce a major conformational change in insulin 2 molecules. RT-PCR studies suggest that both normal and mutant Ins2 alleles are transcribed similarly in pancreatic islets of heterozygous mice, although immunofluorescence and immunoblot analyses of heterozygous islets detected reduced levels of insulin and proinsulin.

Allele

Symbol: Il2rg^tm1Wjl
Name: targeted mutation 1, Warren J Leonard
MGI accession ID: MGI:1857455
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Il2rg
Marker name: interleukin 2 receptor, gamma chain
Chromosome: X
Strain of origin: 129S4/SvJae
Site of expression: Primarily lymphoid cells.
Molecular note: A neomycin resistance cassette replaced part of exon 3 and all of exons 4 - 8 of the gene, resulting in the loss of most of the extracellular domain and all of the transmembrane and cytoplasmic domains of the protein.