Human Molecular Genetics, 2003, Vol. 12, No. 5 483-495
© 2003 Oxford University Press
Defective integrin switch and matrix composition at alpha 7-deficient myotendinous junctions precede the onset of muscular dystrophy in mice
1Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany, 2Department of Anatomy and Cellular Neurobiology, University of Ulm, 89069 Ulm, Germany, 3Department of Histology, University of Göttingen, 37075 Göttingen, Germany, 4Institute of Pathophysiology, University of Greifswald, 17495 Karlsburg, Germany and 5Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK
Received October 18, 2002; Accepted December 17, 2002
Force transmission at the myotendinous junction requires a strong link between the muscle cytoskeleton and the extracellular matrix. At the adult junction, two splice variants of the laminin-binding integrins, 
7Aß1D and 7Bß1D, are highly enriched. The 7 subunits are critical for the integrity of the junctional sarcolemma because integrin 7-deficient mice develop muscular dystrophy, primarily affecting this site of the muscle. Here, we report that ß1D integrin coimmunoprecipitates and colocalizes with the 5 subunit at 7-deficient junctions, but does not associate with 3, 6 or v integrins. By immunogold labelling we show that the basement membranes of integrin 7-deficient muscles recruit abnormally high levels of fibronectin, the ligand of 5ß1D. Finally, we demonstrate that 5ß1D is down-regulated at the normal postnatal junction and is displaced by 7ß1D. These results suggest that the 7 subunit is implicated in the down-regulation of 5ß1D and in the removal of fibronectin from the maturing myotendinous junction, thus providing an 7ß1D-based link to laminin. We propose that the persistence of 5ß1D in 7-deficient mice is not compatible with normal muscle function and leads to muscle wasting.
* To whom correspondence should be addressed at: Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK. Tel: +44 1612755246; Fax: +44 1612753915; Email: ulrike.mayer{at}man.ac.uk
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