STUDIES OF PRODUCTION AND ANALYSIS OF CAVEOLIN-3 AND DYSTROPHIN DEFICIENT MOUSE LINE

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APPROXIMATELY 30GENES, INCLUDING DYSTROPHIN AND CAVEOLIN-3 MUTANT GENES, ARE KNOWN AS THE CAUSES OF MUSCULAR DYSTROPHIES THAT SHOW DEGENERATION, NECROSIS AND REGENERATION OF MUSCLE FIBERS. PREVIOUSLY, WE PRODUCED CAVEOLIN-3 DEFICIENT MICE BY GENE TARGETING TECHNIQUES. IN THIS STUDY, WE ESTABLISHED A MOUSE LINE HAVING DEFECTS IN BOTH DYSTROPHIN AND CAVEOLIN-3 GENES, BY CROSS-BLEEDING OF DYSTROPHIN DEFICIENT MDX MICE AND CAVEOLIN-3 DEFICIENT MICE. USING THIS LINE, WE TRIED TO CLARIFY THE ROLES OF THESE PROTEINS IN THE PATHOLOGY OF MUSCULAR DYSTROPHY. WE FOUND THAT MDX AND THIS LINE MOUSE MUSCLES SHOWED SIMILAR HISTOLOGY. HOWEVER, WE FOUND INTERESTING RESULTS IN THIS LINE, WHEN GENE EXPRESSION WAS ANALYZED. OSTEOPONTIN GENE EXPRESSION WHICH IS KNOWN TO INCREASE ON MUSCLE REGENERATION WAS GREATLY DECREASED IN CAVEOLIN-3 DEFICIENT MUSCLE. IN CONTRAST, IT WAS EXTREMELY ENHANCED IN MDX MUSCLE. PARTICIPATION OF CAVEOLIN-3 IN THE OSTEOPONTIN GENE EXPRESSION WAS FURTHER CLARIFIED BY USING THE DOUBLE DEFICIENT MICE. IN MDX MUSCLE, OSTEOPONTIN GENE EXPRESSION LEVEL INCREASED TO 30-55 TIMES HIGHER THAN THAT OF WILD TYPE MUSCLE, WHEREAS IT RETAINED AT 5-14 TIMES IN THE DOUBLE DEFICIENT MICE. THEREFORE, ABSENCE OF DYSTROPHIN AND CAVEOLIN-3 HAS THE INVERSE EFFECTS ON THE OSTEOPONTIN GENE EXPRESSION AND THUS FOR MUSCLE REGENERATION, ALTHOUGH THE ABSENCE OF EITHER PROTEIN RESULTS IN MUSCULAR DYSTROPHY.