NOD.Cg-Prl^{tm1.1(PRL)Rui} Prkdc^scid Il2rg^tm1Wjl/J

Stock number: 036917
Product name: NSG-Pro
Strain synonyms: NSG-Pro
Research areas: Cancer Research, Endocrine Deficiency Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

NSG-Pro animals combine the features of NSG mice (including the C5 complement deficiency, B and T cell deficiency, and NK cell deficiency) with a targeted knock-in of human Prolactin (hPRL) replacing the mouse Prl gene. This severely immunodeficient strain provides an effective model for human cell transplantation/engraftment and studying ER⁺ breast cancers.

Note that females homozygous for all three mutations are reported to be sterile.

Detailed description

NSG-Pro mice are NOD.scid.Il2Rg^null ("NSG"; Stock No. 005557) animals also harboring a targeted knock-in of the human Prolactin (PRL) gene.

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.

The hormone prolactin (PRL) is implicated in the regulation of numerous biological processes, including reproduction, metabolism, immunology, and behavior, as well as pathologically in certain cancers. Specifically, PRL has been linked to primary growth and metastasis in ER⁺ breast cancers. The donating laboratory has shown that mouse prolactin (mPRL) does not activate hPRL receptors on engrafted ER⁺ tumor cells, but rather acts antagonistically. As such, current patient-derived xenograft (PDX) mouse models do not fully recapitulate the biology and progression of human ER⁺ breast cancers. The donating investigator has created a mouse model, with physiological levels of circulating hPRL in the absence of mPRL, on the NSG background. This model demonstrates a significant increase in engraftment rates, growth, and metastasis of ER⁺ tumors, proving to be a useful tool for testing different treatments for therapy-naïve and drug-resistant ER⁺ breast cancers.

Unmanipulated female mice, that are homozygous for all three targeted mutations, are reported to be sterile but otherwise appear to be healthy with no overt phenotype. Males that are homozygous for the Prl^{tm1.1(PRL)Rui} and Prkdc^scid mutations and hemizygous for the X-linked Il2Rg^null mutation are viable and fertile.

Maintaining these severely immunocompromised mice under specific pathogen-free conditions is recommended to promote their overall health. Please see our NSG housing and breeding information for additional details.

Development

NSG-Pro mice are NOD.scid.Il2Rg^null ("NSG") animals with a targeted knock-in of human Prolactin (PRL) gene. NSG-Pro 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 Il2Rg^null mutation at ~101 Mbp 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 hPRL targeting vector was designed by Dr. Hallgeir Rui (Medical College of Wisconsin) to replace exon 1 of the mouse Prl gene with coding sequence of full-length human PRL gene followed by a floxed neomycin cassette. The construct was electroporated into 129/Sv-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric mice were bred to MMTV-Cre Line A (Stock No. 003551) to remove the neo cassette. The MMTV-cre was subsequently bred out of the colony. The resulting hPRL knock-in mice were backcrossed to NSG mice for at least 10 generations by the donating laboratory. Upon arrival at The Jackson Laboratory, 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: Prl^{tm1.1(PRL)Rui}
Name: targeted mutation 1.1, Hallgeir Rui
MGI accession ID: MGI:7280900
Generation method: Targeted
Attributes: Null/Knockout; Inserted expressed sequence; Humanized sequence
Marker symbol: Prl
Marker name: prolactin
Marker synonyms: Gha1; pPRL; Prl1a1; PRLB; PRLSD1; Prol; RATPRLSD1; RNPROL
Chromosome: 13
Strain of origin: 129S/Sv
Molecular note: The targeting vector is designed to replace exon 1 of the gene with the full-length human PRL coding sequence followed by a floxed neomycin cassette. Cre-mediated recombination removed the neo cassette. Immunoblot analysis indicates that mice do not express endogenous prolactin.