DYSTROPHIC MUSCLE IN MICE CHIMERIC FOR EXPRESSION OF ALPHA-5 INTEGRIN

alpha 5-deficient mice die early in embryogenesis (Yang et al., 1993). To study the functions of alpha 5 integrin later in mouse embryogenes is and during adult life we generated alpha 5 -/-; +/+ chimeric mice. These animals contain alpha 5-negative and positive cells randomly dis tributed. Analysis of the chimerism by glucose-6-phosphate isomerase ( GPI) assay revealed that alpha 5 -/- cells contributed to all the tiss ues analyzed. High contributions were observed in the skeletal muscle. The perinatal survival of the mutant chimeras was lower than for the controls, however the subsequent life span of the survivors was only s lightly reduced compared with controls (Taverna et al., 1998). Histolo gical analysis of alpha 5 -/-;+/+ mice from late embryogenesis to adul t life revealed an alteration in the skeletal muscle structure resembl ing a typical muscle dystrophy. Giant fibers, increased numbers of nuc lei per fiber with altered position and size, vacuoli and signs of mus cle degeneration-regeneration were observed in head, thorax and limb m uscles. Electron microscopy showed an increase in the number of mitoch ondria in some muscle fibers of the mutant mice. Increased apoptosis a nd immunoreactivity for tenascin-C were observed in mutant muscle fibe rs. All the alterations were already visible at late stages of embryog enesis. The number of altered muscle fibers varied in different animal s and muscles and was often increased in high percentage chimeric anim als. Differentiation of alpha 5 -/- ES cells or myoblasts showed that in vitro differentiation into myotubes was achieved normally. However proper adhesion and survival of myoblasts on fibronectin was impaired. Our data suggest that a novel form of muscle dystrophy in mice is alp ha 5-integrin-dependent.