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© The Rockefeller University Press, 0021-9525/1998//849 $5.00
The Journal of Cell Biology, Volume 143, Number 3, , 1998 849-859

Regular Articles

Dystrophic Muscle in Mice Chimeric for Expression of {alpha}5 Integrin



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

* Howard Hughes Medical Institute and Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; {ddagger} 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 || Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

{alpha}5-deficient mice die early in embryogenesis (Yang et al., 1993). 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 (Taverna et al., 1998). 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}5β1 • apoptosis

Abbreviations used in this paper: ECM, extracellular matrix; ES, embryonic stem; FN, fibronectin; GPI, glucose-6-phosphate isomerase; H&E, hematoxylin and eosin; LM, laminin; MTJ, myotendinous junction; PTAH, phosphotungstic acid haematoxylin; TN-C, tenascin-C; WT, wild-type.

The authors wish to acknowledge the excellent technical assistance of K. Mercer and D. Crowley for histology; M. Cummiskey and V. Evans for blastocyst injections; J. Trevithick for immunohistochemistry and P. Reilly for electron microscopy (all from Massachusetts Institute of Technology, Cambridge, MA). We thank A. Chung for the anti-entactin antibody. We are grateful to M. DiPersio and R. Chiquet-Ehrismann for critical reading of the manuscript and B. Bader for helpful discussion.

D. Taverna was supported by Swiss National Foundation, Ciba Geigy Foundation and European Molecular Biology Organization. R.O. Hynes is a Howard Hughes Medical Institute Investigator. This work was supported by the Howard Hughes Medical Institute, by a Program of Excellence (POE) grant (PO1 HL41484) from the National Heart, Lung and Blood Institute and by grants from the Muscular Dystrophy Association and the Department of Veterans Affairs (RAG 9502-010) to T.A. Rando.


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