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J. Cell Biol., Volume 143, Number 3, November 2, 1998 849-859

Dystrophic Muscle in Mice Chimeric for Expression of alpha 5 Integrin

Daniela Taverna,* Marie-Helene Disatnik,Dagger Helen Rayburn,* Roderick T. Bronson,§ Joy Yang,*parallel Thomas A. Rando,Dagger and Richard O. Hynes*

* Howard Hughes Medical Institute and Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; Dagger  Department of Veterans Affairs and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305; § Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111; and parallel  Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

alpha 5-deficient mice die early in embryogenesis (). To study the functions of alpha 5 integrin later in mouse embryogenesis and during adult life we generated alpha 5 -/-;+/+ chimeric mice. These animals contain alpha 5-negative and positive cells randomly distributed. Analysis of the chimerism by glucose- 6-phosphate isomerase (GPI) assay revealed that alpha 5 -/- cells contributed to all the tissues 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 slightly reduced compared with controls (). Histological analysis of alpha 5 -/-;+/+ mice from late embryogenesis to adult life revealed an alteration in the skeletal muscle structure resembling a typical muscle dystrophy. Giant fibers, increased numbers of nuclei per fiber with altered position and size, vacuoli and signs of muscle degeneration-regeneration were observed in head, thorax and limb muscles. Electron microscopy showed an increase in the number of mitochondria in some muscle fibers of the mutant mice. Increased apoptosis and immunoreactivity for tenascin-C were observed in mutant muscle fibers. All the alterations were already visible at late stages of embryogenesis. The number of altered muscle fibers varied in different animals and muscles and was often increased in high percentage chimeric animals. 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 alpha 5-integrin-dependent.

Key words: muscular dystrophy;  chimeric mice;  integrin alpha 5beta 1;  apoptosis


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