This congenic NOD strain contains a neomycin cassette disruption in exon 3 of cathepsin L (Ctsltm1Cptr). NOD Ctsl deficient mice exhibit defective CD4+T cell development and express Foxp3 on CD4+ T cells at a 2 fold higher frequency than controls. Homozygous mice are insulitis and diabetes resistant. This model provides a tool for detailed studies to identify the molecular pathways of major lysosomal cysteine proteases, specifically cathepsin L, in immune modulation.
Dr. Renee C LeBoeuf, Universtiy of Washington
Mice homozygous for this Ctsl targeted mutation are viable, normal in size, and do not display any behavioral abnormalities. Western blot analysis failed to detect any signal in kidneys of homozygous mutant mice. No Ctsl enzymatic activity was detected in the kidney using a synthetic substrate. Donating investigator reports that homozygous females are infertile; while homozygous males breed well. As reported in the B6-Ctsltm1Cptr by Roth et al. 2000, the vibrissae of NOD congenic mutant mice have not penetrated the epidermis at birth and the first emergence of fur is delayed by approximately two days. Beginning around three weeks of age NOD mutant mice begin to lose their fur beginning at the head and progressing toward the tail region. Mature mutant mice are always partially devoid of fur. Unlike the observations of Roth et al. there appears to be no distortion of the the expected rates of homozygous NOD congenic mice weaned. Similar to Maehr et al. 2005, no throiditis, sialadenitis, diabetes or insulitis was detected in NOD.Ctsl deficient females aged to 10 months (Hsing et al, 2009). Ctsl deficient mice exhibit defective CD4+T cell development leading to a reduced CD4:CD8 ratio. CD4+T cells if naive NOD.Ctsl deficient mice exhibit Foxp3 expression at 2 fold higher frequency than wildtype controls (Hsing et al, 2009).
This model provides a tool for detailed studies to identify the molecular pathways of major lysosomal cysteine proteases, specifically cathepsin L in immune modulation.
The Cathepsin L (Ctsl) gene was disrupted via homologous recombination in 129P2/OlaHsd-derived, E14.1 ES cells. A neomycin cassette was inserted into a NcoI site in exon 3 using a SalI linker containing stop codons in all reading frames of the Ctsl gene. The ES cell clone was injected into C57BL/6 blastocysts. The resulting chimeric founder's offspring were bred to C57BL/6J prior to 10 generations of crossing to NOD and intercrossing. Marker assisted analysis indicates 19 known Idd loci are of NOD origin. In 2008, the T1DR received this strain at generation N11F2.
|Allele Name||targeted mutation 1, Christoph Peters|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||CL-; Cat L-; L-; catL-; ctsl-|
|Gene Symbol and Name||Ctsl, cathepsin L|
|Gene Synonym(s)||1190035F06Rik; 1190035F06Rik; CATHL; CATL2; CTSL2; CTSU; Cat L; CatL; Ctsl1; MEP; RIKEN cDNA 1190035F06 gene; fs; furless; major excreted protein; nackt; nkt|
|Strain of Origin||129P2/OlaHsd|
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