Absence of integrin α7 causes a novel form of muscular dystrophy

Integrin α7β1 is a specific cellular receptor for the basement membrane protein laminin-1 (refs 1,2), as well as for the laminin isoforms -2 and -4 (ref. 3). The α7 subunit is expressed mainly in skeletal and cardiac muscle4 and has been suggested to be involved in differentiation and migration processes during myogenesis 5 , 6 .Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle 7 – 9 . In adult muscle, the α7A and α7B subunits are concentrated in myotendinous junctions 10 but can also be detected in neuromuscular junctions and along the sarcolemmal membrane 11 . To study the potential involvement of α7 integrin during myogenesis and its role in muscle integrity and function, we generated a null allele of the α7 gene (ItgaT) in the germline of mice by homologous recombination in embryonic stem (ES) cells. Surprisingly, mice homozygous for the mutation are viable and fertile, indicating that the α7β1 integrin is not essential for myogenesis. However, histological analysis of skeletal muscle revealed typical symptoms of a progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The observed histopathological changes strongly indicate an impairment of function of the myotendinous junctions. These findings demonstrate that αβ1 integrin represents an indispensable linkage between the muscle fibre and the extracellular matrix that is independent of the dystrophin–dystroglycan complex–mediated interaction of the cytoskeleton with the muscle basement membrane.