This congenic NOD strain contains a neomycin cassette that deletes the cathepsin S (Ctsstm1Eae) active site cysteine. NOD Ctss deficient mice exhibit significantly reduced diabetes onset. This model provides a tool for detailed studies to identify the molecular pathways of major lysosomal cysteine proteases, specifically cathepsin S, in immune modulation.
Dr. Renee C LeBoeuf, Universtiy of Washington
Mice homozygous for the Ctss targeted mutation are viable, fertile, normal in size, and do not display any gross physical or behavioral abnormalities.
Cathepsin S activity was not present in splenic cells or LPS induced B cell blasts.
Diabetes incidence in mutant mice was significantly reduced (33%) compared to heterozygous and NOD control females (69%). Histological analysis of the pancreas from non-diabetic mutant females revealed extensive insulitis. Thyroiditis scores were significantly greater while sialadenitis scores were less than NOD wild-type females.
This model provides a tool for detailed studies to identify molecular pathways of major lysosomal cysteine proteases, specifically cathepsin S, in immune modulation.
The Cathepsin S (Ctss) gene (Chromosome 3, 95Mb) was disrupted via homologous recombination in DBA1-252 ES cells. The active site cysteine, was deleted by the insertion of a neomycin selection cassette. The ES cell clone was injected into C57BL/6 blastocysts (Nakagawa et al, 1999). The resulting chimeric founder's and offspring were bred to C57BL/6J prior to 10 generations of crossing to NOD and intercrossing. In 2009, the T1DR received this stock at generation N11F2.
|Allele Name||targeted mutation 1, Eileen A Elliot|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Ctss, cathepsin S|
|Strain of Origin||DBA/1LacJ|
|General Note||The author (Renee LeBoeuf) has confirmed that the allele used in the reference J:153355 was incorrectly reported as Ctsstm1Hap; the correct allele is Ctsstm1Eae .|
|Molecular Note||A neomycin selection cassette replaced a 3.0kb region containing the active site residue. Functional ablation of the protein product in homozygous mutant mice was determined via an active-site labeling assay of splenocytes and LPS B cell blasts.|