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Cited by 178Muscle Physiology and DisordersNeurogenetic and Muscular Disorders ResearchCardiomyopathy and Myosin Studies

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

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Hall, Thomas E., Bryson-Richardson, Robert J., Berger, Silke, Jacoby, Arie S., Cole, Nicholas J., Hollway, Georgina E., Berger, Joachim, Currie, Peter D.·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0700942104PMC PMC1855385
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Abstract

Mutations in the human laminin α 2 ( 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 α 2 ( 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.

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  1. [22]Granato M, van Eeden FJ, Schach U, Trowe T, Brand M, Furutani-Seiki M, Haffter P, Hammerschmidt M, Heisenberg CP, Jiang YJ, et al. (1996) Development (Cambridge, UK) 123:399-413.
  2. [23]Bassett DI, Bryson-Richardson RJ, Daggett DF, Gautier P, Keenan DG, Currie PD (2003) Development (Cambridge, UK) 130:5851-5860.
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Authors
Hall, T. E., Bryson-Richardson, R. J., Berger, S., Jacoby, A. S., Cole, N. J., Hollway, G. E., Berger, J., & Currie, P. D.
Affiliations
  • Victor Chang Cardiac Research Institute (AU)
  • The Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, Sydney NSW 2010, Australia
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2007-04-24
Volume
104
Issue
17
Pages
7092-7097
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0700942104
PMC
PMC1855385
OpenAlex
W2004363672
Cited by
178
References
41
Citations by year
2026: 2 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 7 · 2019: 5 · 2018: 14 · 2017: 13 · 2016: 11 · 2015: 15 · 2014: 13 · 2013: 11 · 2012: 15
FWCI
3.44
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
laminin alpha 2, LAMA2, congenital muscular dystrophy type 1A, zebrafish, extracellular matrix, muscle degeneration, mechanical loading, membrane permeability, apoptosis, myoblast fusion, motor neuron innervation, sarcolemma
MeSH terms
Adhesiveness, Alleles, Amino Acid Sequence, Animals, Base Sequence, Embryo, Nonmammalian, Extracellular Matrix, Gene Expression Regulation, Intercellular Junctions, Laminin, Molecular Sequence Data, Motor Activity, Muscular Dystrophy, Animal, Sarcolemma, Zebrafish, Open Reading Frames, Oligonucleotides, Antisense, Cell Death, Sequence Homology, Amino Acid, Codon, Nonsense, Muscle Fibers, Skeletal, Zebrafish Proteins, Mutant Proteins

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