These Il4raF709 mutant mice harbor a Y709F polymorphism within the canonical immunoreceptor tyrosine-based inhibitory motif (ITIM) sequence near the carboxyl-terminus of the protein. This Y709F polymorphism prevents ITIM phosphorylation and disables the binding of regulatory phosphatases. These Il4raF709 mutant mice may be useful in immunological studies of mitogenic signal transduction, specifically antigen-specific antibody responses, allergic airway inflammation, atopy, asthma, and food allergy research.
Talal Chatila, Boston Children's Hospital
Mice homozygous for this Il4raF709 (IL-4Rα Y709F) polymorphic allele are viable and fertile. The mutation introduces a tyrosine to phenylalanine amino acid substitution at codon 709 (Y709F) within the canonical immunoreceptor tyrosine-based inhibitory motif (ITIM) sequence near the carboxyl-terminus of the protein. This Y709F polymorphism prevents ITIM phosphorylation and inhibit the binding of regulatory phosphatases (including Src homology 2 domain-containing protein tyrosine phosphatase 1 [SHP-1]), resulting in enhanced receptor signaling. Allele-specific PCR verifies the Y709 to F709 codon substitution. Homozygous mice exhibit enhanced phosphorylation of signal transducer and activator of transcription 6 (STAT6) in B cells following IL-4 treatment, and increased serum concentrations of total IgE and ovalbumin (OVA)-specific IgE after immunization with OVA/alum. Il4raF709/F709 mice have increased allergic airway inflammation (peribronchial and perivascular inflammation, goblet cells and eosinophil accumulation) and airway hyperresponsiveness in response to allergen sensitization and challenge.
Both untreated and OVA-challenged homozygous mice exhibit upregulated expression of a number of STAT6-responsive genes involved in allergic airway inflammation. The Y709F substitution results in increased IL-4 production after Th2 polarization (Th2 bias) and enhanced alternative macrophage activiation by IL-13 in vivo.
The Il4raF709/F709 mice are highly susceptible to oral sensitization to OVA, even in the absence of adjuvants, and sensitized mice respond to oral challenge with anaphylaxis. These Il4raF709 mutant mice may be useful in immunological studies of mitogenic signal transduction, specifically antigen-specific antibody responses, allergic airway inflammation, atopy, asthma, and food allergy research.
Two base pair substitutions (A->T and C->T at basepair 2362 and 2363, respectively) were introduced into the murine Il4ra cDNA using site-directed mutagenesis. These mutations result in a single amino acid substitution of tyrosine to phenylalanine at codon 709 (Y709F) within the canonical immunoreceptor tyrosine-based inhibitory motif (ITIM) sequence near the carboxyl-terminus of the protein. A targeting vector that included these two mutations and a loxP-flanked neo cassette inserted into intron 11 was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were transiently transfected with a cre-expressing vector to remove the neo selection cassette (leaving a single loxP site in intron 11) and then injected into recipient blastocysts. The resulting chimeric males were crossed to BALB/cAnNTac females. Heterozygotes were bred to BALB/cAnNTac for at least 10 generations prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred to BALB/cByJ (Stock No. 001026) for at least one generation to establish the colony.
|Allele Name||targeted mutation 3.1, Talal A Chatila|
|Allele Synonym(s)||IL-4Ra Y709F; Il4raF709|
|Gene Symbol and Name||Il4ra, interleukin 4 receptor, alpha|
|Strain of Origin||129X1/SvJ|
|Molecular Note||Two base pair substitutions (A->T and C->T at basepair 2362 and 2363, respectively) were introduced into the murine Il4ra cDNA using site-directed mutagenesis. These mutations result in a single amino acid substitution of tyrosine to phenylalanine at codon 709 (Y709F) within the canonical immunoreceptor tyrosine-based inhibitory motif (ITIM) sequence near the carboxyl-terminus of the protein. The targeting vector included these two mutations and a loxP-flanked neo cassette inserted into intron 11. Cre mdiated recombination removed the neo cassette.|
|Mutations Made By|| |
Talal Chatila, Boston Children's Hospital
When maintaining a live colony, these mice may be bred as homozygotes.
When using the C.129X1-Il4ratm3.1Tch/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #012709 in your Materials and Methods section.
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