Résumé :
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Communication n° 723. The balance between influences that promote or restrain muscle progenitor differentiation is central to correct muscle development. Moreover, detailed understanding of the mechanisms regulating this equilibrium is important for developing new treatments for human muscle diseases, for example, stem cell-based therapy. In order to improve knowledge of the molecular events regulating muscle cell differentiation we are studying a novel gene we isolated in a screen, Dmeso17A. Using the model organism Drosophila melanogaster, we found that Dmeso17A is part of the restraining mechanism of muscle differentiation. Dmeso17A expression rapidly declines in the somatic mesoderm as embryonic muscle differentiates. However, it persists in the adult muscle precursors that are set aside in the somatic mesoderm and which remain undifferentiated at this stage. Consistent with its expression pattern we found that Dmeso17A over-expression inhibits muscle differentiation. This effect is suppressed by over-expression of the Dmef2 transcription factor, the key promoter of muscle differentiation. Moreover, Dmeso17A over-expression phenocopies Dmef2 hypomorphic alleles. These results suggest that Dmeso17A is an inhibitor in the Dmef2-regulated pathway of muscle differentiation. Our model is that Dmeso17A down-regulates Dmef2 activity rather than Dmef2 expression because we found that Dmeso17A inhibits the expression of the Dmef2 target gene beta3tubulin, but has no effect on the expression of Dmef2 itself. We explored the Dmeso17A loss-of-function phenotype through dominant negative and RNAi constructs. These result in aberrant somatic muscle differentiation. We will present details of the phenotypes. How might Dmeso17A be working? It contains a NLS and also a WRPW tetrapeptide motif, which in other proteins interacts with the transcriptional co-repressor Groucho. We found that the Dmeso17A WRPW motif is required for the dramatic inhibitory effect on muscle differentiation. We are now testing whether Dmeso17A interacts with Groucho. Together, our results suggest that Dmeso17A is a novel component of a muscle differentiation switch, and is part of a mechanism that holds cells in an undifferentiated state.
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