Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
PLoS One. 2009 Sep 16;4(9):e7003. doi: 10.1371/journal.pone.0007003.
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.
面肩肱型肌营养不良症（FSHD）是由 4q35.2 处的 D4Z4 重复收缩引起的，据认为这会导致附近基因的失调，其中一个基因 DUX4 实际上位于每个重复内。最近在小鼠 10 号染色体上发现了一个保守的开放阅读框（mDUX），它编码一个双同源结构域蛋白，位于 D4Z4 样重复内。我们在这里表明，高水平的 mDUX 表达诱导成肌细胞死亡，而低水平的非毒性 mDUX 则通过下调 MyoD 和 Myf5 来阻止成肌分化。毒性和 MyoD/Myf5 表达变化可通过过表达 Pax3 或 Pax7 竞争性逆转，这暗示着与人类 DUX4 的抗肌生成活性具有机制相似性。我们测试了 mDUX 表达对非洲爪蟾发育的影响，发现全局过表达导致原肠胚形成异常。当在 16 细胞胚胎的预定成为尾肌的分裂球中单侧靶向表达时，mDUX 导致注射侧的尾肌生成明显减少。这些新的细胞和动物模型突出了与 FSHD 相关重复阵列内序列的肌病性质。
