NOD.Cg-Hgf^{tm1.1(HGF)Aveo} Prkdc^scid Il2rg^tm1Wjl/J

Stock number: 014553
Product name: NSG-hHGFki
Research areas: Cancer Research, Cell Biology Research, Diabetes and Obesity Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

NSG-hHGFki mice are NOD.scid.Il2Rγc^null ("NSG") animals with the Hgf^{tm1.1(HGF)Aveo} "humanized" knock-in allele (hHGFki). Homozygous NSG-hHGFki mice have no mature T cells or B cells, lack functional natural killer (NK) cells, are deficient in cytokine signaling, and express human hepatocyte growth factor (HGF) in place of the endogenous mouse HGF. These mice may be useful in studying the HGF/MET pathway in human tumor xenografts and mouse tumor allografts, as well as examining the ability of anti-HGF to inhibit angiogenesis and other tumor/stroma interactions.

Detailed description

NSG-hHGFki mice are NOD.scid.Il2Rγc^null ("NSG") animals with the Hgf^{tm1.1(HGF)Aveo} "humanized" knock-in allele (hHGFki). NSG-hHGFki females homozygous for all three mutations, and males homozygous for hHGFki, homozygous for scid and hemizygous for the X-linked Il2Rγc^null may be collectively referred to as homozygous NSG-hHGFki mice.

Although viable and fertile, homozygous NSG-hHGFki mice are immunodeficient: they have no mature T cells or B cells, lack functional natural killer (NK) cells, are deficient in cytokine signaling, and express human hepatocyte growth factor (HGF) in place of the endogenous mouse HGF. The endogenous mouse promoter drives expression of human HGF. While the human HGF activates both the human and murine form of its tyrosine kinase receptor (met proto-oncogene (MET; c-Met)), the murine HGF is unable to activate human MET. Mice homozygous for hHGFki express only the human form of HGF. In homozygous hHGFki mice, HGF expression from the knock-in allele is observed in developing embryo, as well as adult liver, kidney and lung. hHGFki homozygous mice exhibit an increase in serum HGF after clotting.

Similar to other immunodeficient strains, maintaining homozygous NSG-hHGFki mice in high health status (specific pathogen-free) vivaria promotes overall colony health. If homozygous NSG-hHGFki animals are maintained in low health barrier rooms, the use of medicated water (e.g., sulfatrim/trimethoprim-sulfa or enrofloxacin/Baytril) is suggested to increase overall colony health. Also see additional NSG housing information.

View our Resources for the NSG mouse model, including discussion forum, immunodeficient model comparison, and categorized, up-to-date references.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

NSG-hHGFki mice are NOD.scid.Il2Rγc^null ("NSG") animals with the Hgf^{tm1.1(HGF)Aveo} "humanized" knock-in allele (hHGFki). NSG-hHGFki mice harbor several mutations, as described below.

NSG mice are non-obese diabetic animals (NOD/ShiLtJ) harboring the spontaneous severe combined immunodeficiency mutation (Prkdc^scid) on chromosome 16 and the Il2Rγc^null mutation on the X chromosome (Il2rg^tm1Wjl created by Dr. Warren J. Leonard [NIH]). NSG mice are described and available from The Jackson Laboratory Repository as Stock No. 005557.

The Hgf^{tm1.1(HGF)Aveo} "humanized" knock-in allele (hHGFki) on chromosome 5 was designed by Dr. William M Rideout III (AVEO Pharmaceuticals, Inc). Briefly, hHGFki mice on a C57BL/6;129S6/SvEvTac background were bred to C3H^scid (C3SnSmn.CB17-Prkdc^scid/J ; Stock No. 001131). The resulting hHGFki;scid double mutant animals on a C3H/HeSnJSmn;C57BL/6;129S6/SvEvTac genetic background are described and available from The Jackson Laboratory Repository as Stock No. 014543.

In 2011, some hHGFki;scid mice (from Stock No. 014543) were bred for ten generation to NSG mice (from Stock No. 005557); the resulting NOD-congenic triple mutant strain (NSG-hHGFki) is Stock No. 014553.

After this, when maintaining the live congenic colony, females homozygous for all three targeted mutations may be bred with males homozygous for hHGFki, homozygous for Prkdc^scid and hemizygous for the X-linked Il2Rγc^null.

Allele

Symbol: Prkdc^scid
Name: severe combined immunodeficiency
MGI accession ID: MGI:1857113
Generation method: Spontaneous
Marker symbol: Prkdc
Marker name: protein kinase, DNA activated, catalytic polypeptide
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
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.

Allele

Symbol: Hgf^{tm1.1(HGF)Aveo}
Name: targeted mutation 1.1, AVEO Pharmaceuticals Inc
MGI accession ID: MGI:4939654
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Hgf
Marker name: hepatocyte growth factor
Chromosome: 5
Strain of origin: 129S6/SvEvTac
Expressed genes: HGF,hepatocyte growth factor,human
Molecular note: A targeting vector was designed to replace exons 3-6 of the mouse hepatocyte growth factor (Hgf) locus with a cDNA sequence encoding exons 2-18 of the human hepatocyte growth factor (HGF), a polyA signal, and a frt-flanked PGK-neo cassette. Flp-mediated recombination removed the neo cassette.
General note: ES cells = JB26A10 (129S6/SvEvTac)