Dmeso17A : a novel inhibitor of Drosophila muscle differentiation

Muscle differentiation is a complex process finely tuned by the interplay of positive and negative factors. Although key positive regulators have been identified, there is rather little evidence of restraining molecules that can control the time and place of muscle differentiation. Identification of such molecules and analysis of their function during muscle differentiation is therefore necessary to gain new insight into the molecular events that regulate this process. My work centred on a gene, Dmeso17A that was identified in the Taylor laboratory in a screen to isolate novel genes specifically expressed in muscle progenitors in Drosophila (Taylor, 2000). Its pattern of expression suggested it could be an inhibitor of muscle development. My aim was to analyse both the role and mechanism of action of Dmeso17A. Dmeso17A expression rapidly declines as muscle differentiation starts, but persists in the adult muscle precursors that remain undifferentiated at this stage. Using the GAL4/UAS system (Brand and Perrimon, 1993) to both mis-express and over-express either full-length or modified proteins, I show that Dmeso17A is a novel co-repressor that inhibits muscle progenitor differentiation. Dmef2, the key promoter of muscle differentiation, can suppress Dmeso17A inhibitory effect on muscle development. This was quantitated by a hatching and survival assay. Moreover, I show that Dmeso17A can down-regulate DMef2 activity. Dmeso17A protein contains a WRPW motif. I show that this motif is functionally important and is required for the interaction of Dmesol7A with the co-repressor Groucho. Finally, I show that Dmeso17A genetically interacts with Histone Deacetylases (HDACs), which are known to bind and down-regulate Mef2 in vertebrates. My model is that Dmeso17A down-regulates DMef2 activity through interactions with Groucho and HDACs, and therefore is a component of an inhibitory complex that holds muscle precursors in an undifferentiated state until cues trigger their differentiation.EThOS - Electronic Theses Online ServiceGBUnited Kingdo