NOD.Cg-Tg(SOD1*G93A)1Gur Prkdc^scid Il2rg^tm1Wjl/SentJ

Stock number: 041590
Product name: mSOD1-NSG
Research areas: Cancer Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Neurobiology Research, Research Tools, Virology Research

Description

mSOD1-NSG mice express a G93A mutant form of human SOD1 on the immunodeficient NSG background. These mice may be useful when studying neuromuscular disorders such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease) and evaluating relevant human cell-based therapeutics.

Detailed description

mSOD1-NSG mice are NOD.scid.Il2Rg^null ("NSG"; Stock No. 005557) animals also harboring a SOD1-G93A transgene (Stock No. 004435). The SOD1-G93A founder line (often referred to as G1H) is reported to have high transgene copy number.

NSG mice are immunodeficient; they have no mature T cells or B cells, lack functional natural killer (NK) cells, have reduced numbers of lymphocytes and myeloid dendritic cells, and are deficient in cytokine signaling. The NSG platform is permissive for xenograft/human tumor growth and for evaluating human cell-based therapeutics. The SOD1-G93A transgene allows for expression of the human superoxide dismutase 1, soluble (SOD1) gene, harboring the G93A mutation, under direction of the human SOD1 promoter. The G93A variant is linked to familial amyotrophic lateral sclerosis (ALS).

Mice that are hemizygous for the SOD1-G93A transgene [Tg(SOD1*G93A)], homozygous for the Prkdc^scid allele, and homozygous (or hemizygous) for the X-linked Il2rg^tm1Wjl knock-out allele are viable and fertile. Mice hemizygous for the SOD1-G93A transgene demonstrate paralysis due to motor neuron degeneration beginning ~11-13 weeks of age with an overall survival of 12-16 weeks of age. Due to the severity of the phenotype, and the poor maternal behavior of females harboring the SOD1-G93A transgene, it is recommended that this line is maintained by breeding females that are non-carrier (WT) for Tg(SOD1*G93A); homozygous Prkdc^scid; homozygous Il2rg^tm1Wjl with males that are hemizygous for Tg(SOD1*G93A); homozygous Prkdc^scid; hemizygous Il2rg^tm1Wjl. Male mice that are hemizygous for Tg(SOD1*G93A) may only be viable as breeders up to ~11 weeks of age due to onset of ALS phenotype.

mSOD1-NSG mice may be useful in studying neuromuscular disorders such as ALS (Lou Gehrig's Disease) and for evaluating respective human cell-based therapeutics.

These mice are severely immunocompromised. SPF (specific pathogen-free) husbandry conditions are recommended. Please see our NSG housing and breeding information for additional details.

Development

The mSOD1-NSG mouse line was generated by backcrossing hemizygous SOD1-G93A transgenic mice (Stock No. 004435) on to an NSG (Stock No. 005557) background for at least 8 generations. Additional details about the alleles expressed in this mouse line are listed below.

The SOD1-G93A (or G93A-SOD1) transgene was designed with a mutant human SOD1 gene (harboring a single amino acid substitution of glycine to alanine at codon 93) driven by its endogenous human SOD1 promoter. This transgene was injected into fertilized B6SJLF1 mouse eggs and founder animals were obtained. Transgenic mice on a mixed B6SJL genetic background were sent to The Jackson Laboratory (as Stock No. 002726). Upon arrival, some mice were backcrossed to C57BL/6J for at least 10 generations to generate the C57BL/6J-congenic strain (Stock No. 004435). This line carries a high copy number and maps to Mus Chr12:97,165,800 (coordinates from MGSC ver 37, mm9).

NSG mice are non-obese diabetic animals (NOD/ShiLtJ) harboring the spontaneous severe combined immunodeficiency mutation (Prkdc^scid) on chromosome 16 and the Il2Rg^null mutation at ~101 Mbp on the X chromosome (Il2rg^tm1Wjl created by Dr. Warren J. Leonard [NIH]).

Dr. Charles Sentman acquired some hemizygous B6-congenic SOD1-G93A transgenic mice (Stock No. 004435), along with some NSG mice, and continuously backcrossed the SOD1-G93A transgene on to the NSG background for at least 8 generations. Donor males that were hemizygous for Tg(SOD1*G93A), homozygous for Prkdc^scid and hemizygous for the X-linked Il2rg^tm1Wjl alleles were provided to The Jackson Laboratory. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize NSG oocytes (Stock No. 005557).

Allele

Symbol: Prkdc^scid
Name: severe combined immunodeficiency
MGI accession ID: MGI:1857113
Generation method: Spontaneous
Synonyms: scid
Marker symbol: Prkdc
Marker name: protein kinase, DNA activated, catalytic polypeptide
Marker synonyms: DNAPDcs; DNAPK; DNA-PK; DNAPKc; DNA-PKC; DNA-PKcs; DNPK1; DOXNPH; dxnph; HYRC; HYRC1; IMD26; p350; S473K; slip; XRCC7
Chromosome: 16
Strain of origin: C.BKa-Igh^b/Icr
Site of expression: T and B lymphocytes.
Molecular note: A T-to-A transversion point mutation at a position corresponding to codon 4046 (codon 4095 in transcript ENSMUST00000023352.8) created a premature stop codon (p.Y4046*).

Allele

Symbol: Il2rg^tm1Wjl
Name: targeted mutation 1, Warren J Leonard
MGI accession ID: MGI:1857455
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: [KO]gammac; CD132^-; gammac^-; gc^-; Il2rg^tm1Wjll; IL2Rgamma^null
Marker symbol: Il2rg
Marker name: interleukin 2 receptor, gamma chain
Marker synonyms: [g]c; Ab2-183; Cd132; CIDX; common cytokine receptor gamma chain; common gamma chain; gamma C receptor; gamma(c); gammaC; gc; IL-2RG; IMD4; P64; SCIDX; SCIDX1
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.

Allele

Symbol: Tg(SOD1*G93A)1Gur
Name: transgene insertion 1, Mark E Gurney
MGI accession ID: MGI:2183719
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: (G93A)Tg+; G1H; G93A; G93A SOD1; G93A+; G93A-SOD1; Gur1-G93A; hSOD1G93A; SOD1 G93A; SOD1 Tg; SOD1^G93A; Tg(G93A-SOD1)1Gur; Tg(SOD1-G93A)1Gur; TgN(SOD1-G93A)1Gur; TgN[SOD1-G93A]1Gur
Marker symbol: Tg(SOD1*G93A)1Gur
Marker name: transgene insertion 1, Mark E Gurney
Marker synonyms: (G93A)Tg+; G1H; G93A; G93A SOD1; G93A+; G93A-SOD1; hSOD1G93A; SOD1 G93A; SOD1 Tg; SOD1^G93A; Tg(G93A-SOD1)1Gur; Tg(SOD1-G93A)1Gur; TgN(SOD1-G93A)1Gur; TgN[SOD1-G93A]1Gur
Chromosome: 12
Strain of origin: (C57BL/6 x SJL)F1
Expressed genes: SOD1,superoxide dismutase 1,human
Molecular note: This transgenic subline (designated G1H in J:76718) is derived from the G1 parental transgenic line (originally described in J:32665). This line carries a 40% expansion in transgene copy number compared to the original G1 line (described in J:32665, in MGI as Tg(SOD1*G93A)2Gur). The transgene construct is composed of the human SOD1 gene carrying a glycine to alanine transition at position 93 (G93A). The G93A mutation does not alter the activity of the protein. This line carries a high copy number maps to Mus Chr12:97,165,800 (coordinates from MGSC ver 37, mm9).
General note: This line, G1H, was derived from the original G1 line (now designated Tg(SOD1*G93A)2Gur) reported in J:32665.

Transgenic mice on a background that involves C57BL/6 and SJL express high levels of the transgene with a 4-fold increase in SOD activity, and exhibit a phenotype similar to amyotrophic lateral sclerosis (ALS) in humans. Hemizygous transgenic mice become paralyzed in one or more limbs and have a life span of approximately 19-23 weeks. Paralysis is due to loss of motor neurons from the spinal cord.