Mutations in laminin-α2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with laminin-α2 are dystroglycan and α7β1 integrin. We have previously shown in mouse models for MDC1A that muscle-specific overexpression of a miniaturized form of agrin (mini-agrin), which binds to dystroglycan but not to α7β1 integrin, substantially ameliorates the disease (Moll, J., P. Barzaghi, S. Lin, G. Bezakova, H. Lochmuller, E. Engvall, U. Muller, and M.A. Ruegg. 2001. Nature. 413:302–307; Bentzinger, C.F., P. Barzaghi, S. Lin, and M.A. Ruegg. 2005. Matrix Biol. 24:326–332.). Now we show that late-onset expression of mini-agrin still prolongs life span and improves overall health, although not to the same extent as early expression. Furthermore, a chimeric protein containing the dystroglycan-binding domain of perlecan has the same activities as mini-agrin in ameliorating the disease. Finally, expression of full-length agrin also slows down the disease. These experiments are conceptual proof that linking the basement membrane to dystroglycan by specifically designed molecules or by endogenous ligands, could be a means to counteract MDC1A at a progressed stage of the disease, and thus opens new possibilities for the development of treatment options for this muscular dystrophy.
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26 March 2007
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March 26 2007
Linker molecules between laminins and dystroglycan ameliorate laminin-α2–deficient muscular dystrophy at all disease stages
Sarina Meinen,
Sarina Meinen
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
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Patrizia Barzaghi,
Patrizia Barzaghi
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
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Shuo Lin,
Shuo Lin
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
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Hanns Lochmüller,
Hanns Lochmüller
2Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany
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Markus A. Ruegg
Markus A. Ruegg
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
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Sarina Meinen
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Patrizia Barzaghi
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Shuo Lin
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Hanns Lochmüller
2Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany
Markus A. Ruegg
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Correspondence to Markus A. Ruegg: [email protected]
Abbreviations used in this paper: c-FLag, chick full-length muscle agrin; c-mag, chick mini-agrin; CK, creatine kinase; CMD, congenital muscular dystrophy; DGC, dystrophin–glycoprotein complex; DMD, Duchenne muscular dystrophy; dMyHC, developmental myosin heavy chain; HE, hematoxylin and eosin; MCK, muscle CK; m-mag, mouse mini-agrin; tTA, tetracycline-dependent transcription activator; WT, wild-type.
Received:
November 28 2006
Accepted:
February 12 2007
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2007
J Cell Biol (2007) 176 (7): 979–993.
Article history
Received:
November 28 2006
Accepted:
February 12 2007
Citation
Sarina Meinen, Patrizia Barzaghi, Shuo Lin, Hanns Lochmüller, Markus A. Ruegg; Linker molecules between laminins and dystroglycan ameliorate laminin-α2–deficient muscular dystrophy at all disease stages . J Cell Biol 26 March 2007; 176 (7): 979–993. doi: https://doi.org/10.1083/jcb.200611152
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