title: Biphasic myopathic phenotype of mouse DUX, an ORF within conserved FSHD-related repeats.
abstract: 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.
authors.affiliation: Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Darko
authors.initials: D
authors.lastname: Bosnakovski
authors.forename: Randy S
authors.initials: RS
authors.lastname: Daughters
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xu
authors.forename: Jonathan M W
authors.initials: JM
authors.lastname: Slack
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics; D017570:MyoD Protein / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics; D016366:Open Reading Frames; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D014982:Xenopus laevis
chemical_list: C532958:Dux4 protein, mouse; D018398:Homeodomain Proteins; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051787:Myogenic Regulatory Factor 5; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; C497322:Pax7 protein, mouse; C068686:Pax3 protein, mouse