Abstract(s) :

(Anglais) The pathogenic mechanisms underlying facioscapulohumeral muscular dystrophy (FSHD) are unclear. Predominant pathogenesis models support FSHD is caused by genetic and epigenetic abnormalities that ultimately increase expression of genes with myotoxic potential. Several putative 'FSHD genes' have been identified, but none are conclusively linked to FSHD development. Here, we provide in vivo evidence that over-expression of the FSHD candidate gene DUX4, which encodes a transcription factor, recapitulates features of muscular dystrophy in zebrafish and mice. In addition, we show that DUX4-associated toxicity requires its DNA binding ability, since over-expression of a DUX4 DNA binding domain mutant (DUX.HOX1) produced no abnormalities in vitro or in vivo. These results suggested that DUX4 transactivates downstream genes that are incompatible with normal muscle development and/or maintenance. Using real-time PCR arrays, we found that numerous genes in the p53 pathway were elevated in muscles over-expressing DUX4, but not mutant DUX4.HOX1, supporting that DUX4 transcriptional activity directly or indirectly activates apoptosis in vivo. Importantly, we show that the myopathic effects of DUX4 are p53-pathway dependent, since muscles from p53 null mice were resistant to the DUX4-induced damage we observed in wild-type mice. These results are consistent with previous observations that some p53 pathway components are activated in muscles from FSHD patients. Together, our data support that DUX4 over-expression contributes to FSHD development, and justify further investigation of p53 pathway involvement in FSHD.