PUBLICATION

The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin {alpha}2-deficient congenital muscular dystrophy

Authors
Hall, T.E., Bryson-Richardson, R.J., Berger, S., Jacoby, A.S., Cole, N.J., Hollway, G.E., Berger, J., and Currie, P.D.
ID
ZDB-PUB-070427-21
Date
2007
Source
Proceedings of the National Academy of Sciences of the United States of America   104(17): 7092-7097 (Journal)
Registered Authors
Berger, Joachim, Berger, Silke, Bryson-Richardson, Robert, Cole, Nicholas, Currie, Peter D., Hall, Thomas, Jacoby, Arie
Keywords
muscle, degeneration, fiber, time-lapse
MeSH Terms
  • Intercellular Junctions/drug effects
  • Intercellular Junctions/ultrastructure
  • Base Sequence
  • Laminin/chemistry
  • Laminin/deficiency*
  • Laminin/genetics
  • Laminin/metabolism
  • Extracellular Matrix/drug effects
  • Extracellular Matrix/metabolism*
  • Sequence Homology, Amino Acid
  • Cell Death/drug effects
  • Oligonucleotides, Antisense/pharmacology
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/innervation
  • Embryo, Nonmammalian/ultrastructure
  • Zebrafish/abnormalities*
  • Zebrafish/embryology
  • Animals
  • Sarcolemma/drug effects
  • Sarcolemma/pathology
  • Muscular Dystrophy, Animal/congenital*
  • Alleles
  • Muscle Fibers, Skeletal/drug effects
  • Muscle Fibers, Skeletal/pathology
  • Amino Acid Sequence
  • Mutant Proteins/metabolism*
  • Adhesiveness/drug effects
  • Codon, Nonsense/genetics
  • Motor Activity/drug effects
  • Zebrafish Proteins/metabolism*
  • Open Reading Frames/genetics
  • Gene Expression Regulation/drug effects
  • Molecular Sequence Data
(all 34)
PubMed
17438294 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Mutations in the human laminin alpha2 (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 alpha2 (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.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ed6TgTransgenic Insertion
    ta222a
      Point Mutation
      teg15a
        Point Mutation
        tk209
          Point Mutation
          1 - 4 of 4
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          Human Disease / Model
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          lama2MO1-lama2MRPHLNO
          lama2MO3-lama2MRPHLNO
          1 - 2 of 2
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          Fish
          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          GAL4EFGGAL4
          1 - 2 of 2
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          Mapping
          Entity Type Entity Symbol Location
          Featureteg15aChr: 20 Details
          Featuretk209Chr: 20 Details
          SSLPz6804Chr: 20 Details
          SSLPz7603Chr: 20 Details
          SSLPz9708Chr: 20 Details
          1 - 5 of 5
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