Absence of integrin alpha 7 causes a novel form of muscular dystrophy.
Integrin alpha 7 beta 1 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 alpha 7 subunit is expressed mainly in skeletal and cardiac muscle and has been suggested to be involved in differentiation and migration processes during myogenesis. Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle. In adult muscle, the alpha 7A and alpha 7B subunits are concentrated in myotendinous junctions but can also be detected in neuromuscular junctions and along the sarcolemmal membrane. To study the potential involvement of alpha 7 integrin, during myogenesis and its role in muscle integrity and function, we generated a null allele of the alpha 7 gene (Itga7) 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 alpha 7 beta 1 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 alpha 7 beta 1 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.
Mayer
U
U
Max-Planck-Institute for Biochemistry, Martinsried, Germany. Mayer@biochem.mpg.de
Saher
G
G
Fässler
R
R
Bornemann
A
A
Echtermeyer
F
F
von der Mark
H
H
Miosge
N
N
Pöschl
E
E
von der Mark
K
K
D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D005121:Extremities / Q000473:pathology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006720:Homozygote; D039001:Integrin alpha Chains; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics*; D010587:Phagocytosis; D011995:Recombination, Genetic; D019063:Tenascin / Q000378:metabolism; D013710:Tendons / Q000473:pathology
D015703:Antigens, CD; D039001:Integrin alpha Chains; D019063:Tenascin; C085725:integrin alpha7