The need for better therapies to treat muscle wasting is growing, a need driven by diseases such as muscular dystrophy, by chemotherapies and by the rapidly aging populations of the developed world. Successful new therapies will generate myoblasts that fuse the appropriate number of times and reshape the targeted muscles. A barrier to developing those therapies, however, is the missing critical information about how myoblasts translate their identity information into a muscle's size, shape, orientation and association with surrounding cells, i.e., characteristics collectively called a muscle's morphology. The goal of this proposal is to connect the genes that control identity to the processes that elaborate the muscle morphology. This will result in an understanding the genes and processes critical to acquisition of size and shape during both development and disease. Drosophila muscle morphogenesis is a highly effective model system to use in this investigation, due to the unique genetic, cellular, and genomic approaches that it affords. Based on published and preliminary data, we propose that the combined activities of 5 transcriptional regulators, Kruppel, Twist, Apterous, Caupolican, and Muscle Segment Homeobox, control the morphogenesis of the lateral muscles. We will categorize the muscle attributes (size, shape, orientation or attachment) that are affected by each regulator. We will determine which of these factors regulate each other and which collaborate to regulate distinct aspects of muscle morphogenesis. We then will determine which aspects of FC cellular behavior are controlled by these regulators during morphogenesis. Lastly, we will begin to identify target genes regulated by these FC identity regulators. Taken together, a picture will emerge of the processes and the genes that regulate specific morphological characteristics. Our work will have direct application to vertebrate muscle morphogenesis and therapies, and to the mechanisms underlying several human diseases. For example, two cranial-facial disorders, Saethre-Chotzen syndrome and Wolf-Hirschhom Syndrome, have been linked to human TWIST and MSXl(Msh), respectively. Additionally, human Twist has been found to play a central role in tumor metastasis. Our work in Drosophila on the mechanisms and targets of these regulators' action will provide insight as to the underlying causes of these diseases and will help to reveal potential therapies.
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