Biphasic myopathic phenotype of mouse DUX, an ORF within conserved FSHD-related repeats

Facioscapulohumeral muscular dystrophy (FSHD) is caused by contractions of D4Z4 repeats at 4q35.2 thought to induce misregulation of nearby genes, one of which, DUX4, is actually localized within each repeat. A conserved ORF (mDUX), embedded within D4Z4-like repeats, encoding a double-homeodomain pr...

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Bibliographic Details
Published in:PloS one 2009-09, Vol.4 (9), p.e7003
Main Authors: Bosnakovski, Darko, Daughters, Randy S, Xu, Zhaohui, Slack, Jonathan M W, Kyba, Michael
Format: Article
Language:English
Subjects:
Abnormalities
Animal models
Animals
Apoptosis
Biopsy
Blastomeres
Cell Biology
Cell Biology/Gene Expression
Cell culture
Chromosome 10
Chromosome Mapping
Chromosomes - genetics
Developmental biology
Developmental Biology/Cell Differentiation
Developmental Biology/Stem Cells
Dystrophy
Embryos
Gastrulation
Gene expression
Gene Expression Regulation, Developmental
Genes
Genetic aspects
Heart
Homeobox
Homeodomain Proteins - metabolism
Humans
Mice
Muscular dystrophy
Muscular Dystrophy, Facioscapulohumeral - genetics
Musculoskeletal system
MyoD protein
MyoD Protein - metabolism
Myogenesis
Myogenic Regulatory Factor 5 - genetics
Open Reading Frames
Paired Box Transcription Factors - metabolism
Pax3 protein
PAX3 Transcription Factor
PAX7 Transcription Factor - metabolism
Pediatrics
Phenotype
Protein Structure, Tertiary
Proteins
Rodents
Stem cells
Toxicity
Xenopus
Xenopus laevis
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Summary:Facioscapulohumeral muscular dystrophy (FSHD) is caused by contractions of D4Z4 repeats at 4q35.2 thought to induce misregulation of nearby genes, one of which, DUX4, is actually localized within each repeat. A conserved ORF (mDUX), embedded within D4Z4-like repeats, encoding a double-homeodomain protein, was recently identified on mouse chromosome 10. We show here that high level mDUX expression induces myoblast death, while low non-toxic levels block myogenic differentiation by down-regulating MyoD and Myf5. Toxicity and MyoD/Myf5 expression changes were competitively reversed by overexpression of Pax3 or Pax7, implying mechanistic similarities with the anti-myogenic activity of human DUX4. We tested the effect of mDUX expression on Xenopus development, and found that global overexpression led to abnormalities in gastrulation. When targeted unilaterally into blastomeres fated to become tail muscle in 16-cell embryos, mDUX caused markedly reduced tail myogenesis on the injected side. These novel cell and animal models highlight the myopathic nature of sequences within the FSHD-related repeat array.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0007003