These Foxp3K276X (forkhead box P3) mutant mice exhibit multisystem lymphoproliferative and myeloproliferative disease, and have applications in studies of T regulatory (Treg) cell function and allergic inflammation.
Talal Chatila, Boston Children's Hospital
The transcriptional regulator FOXP3 is in the forkhead/winged-helix family and has an important role in T regulatory cells (Tregs) development and function. These mice carry a targeted mutation of the Foxp3 gene that contains the K276X nonsense mutation (A to T substitution in the first base position of codon 276) in exon 8, which creates a stop codon. Female mice that are heterozygous for the mutation are viable and fertile. Male mice carrying this X-linked mutation die within a few weeks after birth, due to aggressive lymphoproliferative and myeloproliferative disease. A significant decrease (>10-fold) in gene product (mRNA) and complete loss of protein is detected by Real-time PCR and FACS analysis of mutant splenocytes. No Foxp3+CD4+CD25+ Treg cells are detected. Mutant male mice exhibit spontaneous allergic airway inflammation, progressive lymphoproliferation and myeloproliferation and blood eosinophilia. Mutant mice exhibit impaired immune response to vaccinia virus challenge, failing to produce virus specific T cells and exhibiting higher viral loads. Male hemizygotes on a congenic C57BL/6 background live longer (up to 60 days) than male hemizygotes on a BALB/c background (up to 23 days).
A targeting vector designed by Dr. Talal A. Chatila (UCLA) containing a loxP flanked NEO cassette was used to introduce the K276X nonsense mutation (A to T substitution in the first base position of codon 276) in exon 8, creating a stop codon. The construct was electroporated into 129X1/SvJ derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric male animals were crossed to C57BL/6 female mice. The mice were then crossed to EIIa-cre deleter mice on a mixed BALB/c, C57BL/6 background to remove the floxed NEO cassette. The donating investigator reported the mice were backcrossed to C57BL/6 mice for 15 generations (see SNP results below) prior to sending males to The Jackson Laboratory Repository in 2013. Upon arrival, males were used to cryopreserve sperm. To establish the living mouse colony, an aliquot of the frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).
In 2013, a 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the first generation rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, all 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating (4 markers heterozygous in all mice; 1 marker heterozygous in some mice). These data suggest that the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.
|Allele Name||targeted mutation 1, Talal A Chatila|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Foxp3tm1Tch; targeted mutation 1, Talal A Chatila|
|Gene Symbol and Name||Foxp3, forkhead box P3|
|Gene Synonym(s)||AIID; sf; DIETER; IPEX; PIDX; scurfin; XPID; JM2; scurfy; RGD1562112|
|Strain of Origin||129X1/SvJ|
|Molecular Note||A vector was designed to change codon K276 to a stop codon in exon 8. A neo included in the vector was subsequently removed via cre mediated recombination.|
When maintaining a live colony, female mice can be bred as heterozygotes. Male mice carrying this X-linked mutation die within a few weeks after birth, due to aggressive lymphoproliferative and myeloproliferative disease.
When using the Foxp3K276X C57BL/6 mouse strain in a publication, please cite the originating article(s) and include JAX stock #019933 in your Materials and Methods section.
|X linked - females Heterozygous for Foxp3<tm1Tch> and males are wildtype|
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