The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin α2-deficient congential muscular dystrophy

Hall, Thomas E., Bryson-Richardson, Robert J., Berger, Silke, Jacoby, Arie S., Cole, Nicholas J., Hollway, Georgina E., Berger, Joachim and Currie, Peter D. (2007) The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin α2-deficient congential muscular dystrophy. Proceedings of the National Academy of Sciences, 104 17: 7092-7097. doi:10.1073/pnas.0700942104

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Author Hall, Thomas E.
Bryson-Richardson, Robert J.
Berger, Silke
Jacoby, Arie S.
Cole, Nicholas J.
Hollway, Georgina E.
Berger, Joachim
Currie, Peter D.
Title The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin α2-deficient congential muscular dystrophy
Formatted title
The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin α2-deficient congential muscular dystrophy
Journal name Proceedings of the National Academy of Sciences   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2007-04-24
Sub-type Article (original research)
DOI 10.1073/pnas.0700942104
Open Access Status File (Publisher version)
Volume 104
Issue 17
Start page 7092
End page 7097
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted abstract
Mutations in the human laminin α2 (LAMA2) gene result in the most common form of congenital muscular dystrophy (MDC1A). There are currently three models for the molecular basis of cellular pathology in MDC1A: (i) lack of LAMA2 leads to sarcolemmal weakness and failure, followed by cellular necrosis, as is the case in Duchenne muscular dystrophy (DMD); (ii) loss of LAMA2-mediated signaling during the development and maintenance of muscle tissue results in myoblast proliferation and fusion defects; (iii) loss of LAMA2 from the basement membrane of the Schwann cells surrounding the peripheral nerves results in a lack of motor stimulation, leading to effective denervation atrophy. Here we show that the degenerative muscle phenotype in the zebrafish dystrophic mutant, candyfloss (caf) results from mutations in the laminin α2 (lama2) gene. In vivo time-lapse analysis of mechanically loaded fibers and membrane permeability assays suggest that, unlike DMD, fiber detachment is not initially associated with sarcolemmal rupture. Early muscle formation and myoblast fusion are normal, indicating that any deficiency in early Lama2 signaling does not lead to muscle pathology. In addition, innervation by the primary motor neurons is unaffected, and fiber detachment stems from muscle contraction, demonstrating that muscle atrophy through lack of motor neuron activity does not contribute to pathology in this system. Using these and other analyses, we present a model of lama2 function where fiber detachment external to the sarcolemma is mechanically induced, and retracted fibers with uncompromised membranes undergo subsequent apoptosis.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 07 Feb 2012, 20:35:09 EST by Susan Allen on behalf of Institute for Molecular Bioscience