Exons 2-4 of the mouse Ltc4s gene were replaced with a neomycin cassette in this targeted mutant strain. Protein expression is significantly reduced. Homozygotes show reduced vascular permeabilities induced by zymosan and IgE cross-linking as well as reduced antigen-induced pulmonary inflammation and bleomycin-induced pulmonary fibrosis.
Yoshihide Kanaoka, Brigham and Women's Hospital
Ltc4s (leukotriene C4 synthase) is the terminal 5-lipoxygenase pathway enzyme that is responsible for the biosynthesis of cysteinyl leukotrienes. Cysteinyl leukotrienes are potent lipid mediators of tissue inflammation, particularly implicated in allergic and asthmatic diseases.
These mice carry a targeted knockout of the mouse gene in which exons 2-4 were replaced with a neomycin cassette in reverse transcriptional orientation. LTC4S activity, assessed by conjugation of leukotriene (LT) A4 methyl ester with glutathione, is absent from tongue, spleen, and brain and more than 90% reduced in lung, stomach, and colon. An unstable mRNA transcript involving exon 5 and presumably the neomycin gene is detectable. Bone marrow-derived mast cells from the mice do not generate LTC4 in response to IgE-dependent activation.
Homozygous knock-out mice (which are viable, fertile, and without apparent abnormalities) show reduced vascular permeabilities induced by zymosan and IgE cross-linking. They also show reduced antigen-induced pulmonary inflammation and bleomycin-induced pulmonary fibrosis.
The phenotype of this BALB/c background strain is reported to be the same as that of the C57BL/6N genetic background line (see Stock No. 030813).
Exons 2-4 of the mouse Ltc4s gene, including Arg-51 in exon 2 and Tyr-93 in exon 4 (critical residues for gene activity), were replaced with a neomycin resistance cassette in reverse transcriptional orientation via homologous recombination in AB2.2 129S7/SvEvBrd-Hprt1b-m2-derived embryonic stem (ES) cell line. Resultant mice were crossed to C57BL/6NCrl for one generation, then this line was backcrossed to BALB/cAnNCrl for 11 generations by the donating laboratory.
|Allele Name||targeted mutation 1, Bing K Lam|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Ltc4s, leukotriene C4 synthase|
|Strain of Origin||129S7/SvEvBrd-Hprtb-m2|
|Molecular Note||A neomycin gene cassette replaced 289 nucleotides from intron 1 as well as exons 2 through 4 and 32 nucleotides from intron 4. Northern blot analysis of RNA from bone marrow macrophages confirmed the absence of normal transcripts. An exon 5 containing transcript was produced however. No leukotriene C4 was detectable.|
Homozygotes and heterozygotes are viable and fertile.
When using the LTC4S- mouse strain in a publication, please cite the originating article(s) and include JAX stock #030959 in your Materials and Methods section.
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