Case Study 1
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Dilated cardiomyopathy in RAG-1-/- mice
? Viral ? Genetic
Sporadic occurrence in up to 20% of mice
Increased incidence after extensive backcrossing
to B10.BR - almost universal on histopathology,
and clinically apparent particularly in female
breeding stock
• Unable to segregate RAG-1-/- and cardiomyopathy,
no way to genotype for susceptibility to
cardiomyopathy
• Fortunately, RAG-1-/- subline sent to ARC was free
of cardiomyopathy. Entire backcross to B10.BR
was repeated starting with breeding nucleus from
ARC
Case Study 2
• Colitis in RAG-1-/- colony
• Originally suspected due to Citrobacter but
microbiological tests negative
• Genetic analysis of every case in past 12 months
revealed that colitis occurred only in mice with a
particular genotype - T cell receptor transgenic with T
cells produced by the thymus
• Solution 1: breed T cell receptor transgenic colony on
a background that does not produce T cells in the
thymus, and cross onto T-producing background only
when necessary to produce experimental mice. Use
mice in experiments before onset of colitis
• Solution 2: Infection with Helicobacter identified as a
necessary co-factor for development of colitis. Csection colony onto Helicobacter-negative foster
mothers from ARC
Case Study 3
• Early death in homozygous CTLA-4-/- mice due to abnormal
immune activation
• Occurrence of pathology and need for technically difficult
genetic screening in breeding colonies led to problems
identifying sick animals quickly enough, maintaining lines and
generating sufficient homozygous mice for experiments
• Solution: Breed two homozygous colonies of CTLA-4-/- mice on
RAG-1-/- and RAG-2-/- backgrounds, respectively. The lack of
immune system prevents immune pathology due to abnormal
immune activation. When mice needed for experiments,
intercross the lines on RAG-1-/- and RAG-2-/- backgrounds.
This generates RAG-1+/- and RAG-2+/- mice with an immune
system. All mice will be homozygous CTLA-4-/-, and
experiments can be planned knowing how many mice are
available.
• Note - total number of mice bred while establishing CTLA-4-/lines on RAG-1-/- and RAG-2-/- backgrounds was significantly
larger than required to maintain the previous strategy