Dystrophin is required for the formation of stable muscle attachments in the zebrafish embryo.
A class of recessive lethal zebrafish mutations has been identified in which normal skeletal muscle differentiation is followed by a tissue-specific degeneration that is reminiscent of the human muscular dystrophies. Here, we show that one of these mutations, sapje, disrupts the zebrafish orthologue of the X-linked human Duchenne muscular dystrophy (DMD) gene. Mutations in this locus cause Duchenne or Becker muscular dystrophies in human patients and are thought to result in a dystrophic pathology through disconnecting the cytoskeleton from the extracellular matrix in skeletal muscle by reducing the level of dystrophin protein at the sarcolemma. This is thought to allow tearing of this membrane, which in turn leads to cell death. Surprisingly, we have found that the progressive muscle degeneration phenotype of sapje mutant zebrafish embryos is caused by the failure of embryonic muscle end attachments. Although a role for dystrophin in maintaining vertebrate myotendinous junctions (MTJs) has been postulated previously and MTJ structural abnormalities have been identified in the Dystrophin-deficient mdx mouse model, in vivo evidence of pathology based on muscle attachment failure has thus far been lacking. This zebrafish mutation may therefore provide a model for a novel pathological mechanism of Duchenne muscular dystrophy and other muscle diseases.
Comparative and Developmental Genetics Section, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. dbassett@hgu.mrc.ac.uk
David I
DI
Bassett
Robert J
RJ
Bryson-Richardson
David F
DF
Daggett
Philippe
P
Gautier
David G
DG
Keenan
Peter D
PD
Currie
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009124:Muscle Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010802:Phylogeny; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D016415:Sequence Alignment; D019076:Transgenes; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*
D046911:Macromolecular Substances; D008565:Membrane Proteins; D009124:Muscle Proteins; D011993:Recombinant Fusion Proteins; D029961:Zebrafish Proteins; C435224:dmd protein, zebrafish