B6.Cg-Fcgrt^tm1Dcr Prkdc^scid Tg(CAG-FCGRT)276Dcr/DcrJ

Stock number: 021146
Product name: FcRn-/- hFcRn (line 276) Tg scid
Research areas: Cell Biology Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

FcRn-/- hFcRn (line 276) Tg scid mice express a human alpha chain FCGRT molecule in lieu of the endogenous mouse Fcgrt. The presence of the Prkdc^scid allele conveys immunodeficiency. These mice are useful in applications involving xenograft studies, in evaluating the pharmacokinetics and pharmacodynamics of human immunoglobulin (Ig) and Fc-domain based therapeutics, and for testing of potential immunogenic human IgGs.

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Detailed description

These mice are homozygous for a FcRn alpha-chain knockout allele (Fcgrt^tm1Dcr), the Prkdc^scid allele, and express a human FcRn alpha-chain (FCGRT) transgene under the control of the CAG promoter/enhancer (line 276). Mice display a normal level of murine serum albumin, and a low level of murine IgG due to species-specific binding of IgG by human FCGRT, i.e. murine IgG has a very low affinity to human FCGRT and therefore is not recycled. The transgenic founder line 276 provides a model to study serum half-life of human IgG (hIgG), with a good correlation to cynomolgus monkey and human. This mouse model is useful for studying human FcRn biology and the behavior of IgG antibodies and Fc-domain proteins. These immunocompromised, humanized mice produce no mature T cells or B cells and may be useful in xenograft studies, for testing of potential immunogenic hIgGs, and in evaluating the pharmacokinetics of human immunoglobulin and Fc-domain based therapeutics.

Development

These knockout/transgenic mice were generated in the laboratory of Dr. Derry Roopenian (The Jackson Laboratory) by crossing B6.Cg-Fcgrt^tm1Dcr Tg(CAG-FCGRT)279Dcr/DcrJ mice (Stock No. 004919) to B6.Cg-Fcgrt^tm1Dcr Prkdc^scid/DcrJ (Stock No. 018541).

To generate the FcRn alpha-chain knockout mice (Fcgrt^tm1Dcr; see also Stock No. 003982), a targeting vector was designed to replace 1588 nucleotide fragments (encoding promoter sequence 5' of the transcriptional start site, exon1, intron 2, and most of exon2) with a PGK-Neo^r cassette. The vector was electroporated into 129/SvJ-derived ESV/J-1182 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice (Roopenian et al. J Immunol. 2003 Apr 1;170(7):3528-33).

To generate the hFcRn line 276 transgenic mice, a transgene was designed with the 0.34 kb human cytomegalovirus immediate early promoter enhancer, 1.4 kb chicken beta-actin promoter and intron 1, a cDNA sequence encoding the human FcRn alpha-chain, 0.73 kb rabbit beta-globin intron, and 0.35 kb SV40 polyA sequence. The donating investigator reports that this transgene was injected into C57BL/6J embryos. The resulting transgenic offspring were bred to C57BL/6J mice to establish founder line 276. These hFcRn line 276 transgenic mice were maintained on a C57BL/6J genetic background prior to breeding with mice carrying the Fcgrt^tm1Dcr allele (B6.Cg-Fcgrt^tm1Dcr Tg(CAG-FCGRT)279Dcr/DcrJ, see also Stock No. 004919). Prkdc^scid occurred spontaneously in a colony of BALB/c-Ighb (C.B-17) mice maintained at the Institute for Cancer Research in Philadelphia, PA. The mutation was transferred to the C57BL/6J background by an initial cross between C.B-17-Prkdc^scid/Prkdc^scid and C57BL/6J followed by sequential backcrossing of heterozygous animals of the F1 and male heterozygotes (identified by test crossing) of subsequent generations to C57BL/6J. At the 10th backcross generation the mutation was made homozygous by brother-sister inbreeding (Stock No. 001913).

Allele

Symbol: Tg(CAG-FCGRT)276Dcr
Name: transgene insertion 276, Derry C Roopenian
MGI accession ID: MGI:4441040
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: hFcRn (276) Tg; Tg276
Marker symbol: Tg(CAG-FCGRT)276Dcr
Marker name: transgene insertion 276, Derry C Roopenian
Marker synonyms: hFcRn (276) Tg
Chromosome: 1
Strain of origin: C57BL/6J
Expressed genes: FCGRT,Fc fragment of IgG receptor and transporter,human
Molecular note: To generate the hFcRn line 276 transgenic mice, a transgene was designed with the 0.34 kb human cytomegalovirus immediate early promoter enhancer, 1.4 kb chicken beta-actin promoter and intron 1, a cDNA sequence encoding the human FcRn alpha-chain, 0.73 kb rabbit beta-globin intron, and 0.35 kb SV40 polyA sequence. Line 276 was established. Transgene insertion occurred on Chr 1, causing a 1 bp duplication.

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: Fcgrt^tm1Dcr
Name: targeted mutation 1, Derry C Roopenian
MGI accession ID: MGI:3511510
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: FcRn^-
Marker symbol: Fcgrt
Marker name: Fc receptor, IgG, alpha chain transporter
Marker synonyms: alpha-chain; FcgammaRn; FCRN; neonatal Fc receptor
Chromosome: 7
Strain of origin: 129X1/SvJ
Molecular note: Sequence from exon 1 and part of exon2 was replaced with a PGK-neo cassette. Quantitative PCR of liver cDNA indicated the absence of mRNA. Western blot analysis of neonatal intestinal extracts failed to reveal protein product.