The establishment of the intricate muscle patterns found in higher organisms occurs as migrating muscle cells are guided towards specific sites of attachment. Relatively few molecules have been identified that guide this process and little is known about the molecular mechanisms that govern the different responses that individual migrating muscle fibers have to these extra-cellular guidance cues. A great deal of this information comes from studies in the fruit fly where highly effective genetic and in vivo imaging methods can be used to undertake this important issue in developmental biology. While the early steps of muscle cell determination differ between insects and vertebrates, the later steps of muscle guidance and attachment are surprisingly similar. This remarkable conservation, combined with the straightforward visualization of muscle patterning defects, and the substantial availability of molecular and genetic tools, make the fruit fly an attractive model system for the study of muscle attachment site specificity. Two approaches are proposed to study the molecular basis of the responses that muscle fibers have to external guidance cues. We have found that Slit, an evolutionary conserved extra-cellular matrix protein that functions as both an attractive and repulsive guidance cue for cells in many different tissues, plays an important role in Drosophila muscle migration. We propose to study the details of Slit's role in muscle migration and in addition, we would like to identify and characterize new molecules that play a role in this process. The identification of new molecules and mechanisms that participate in Drosophila muscle guidance promises new insights into muscle development that are like to also be relevant in vertebrates. Specifically, they may provide new targets or strategies for designing therapeutics for muscle diseases such as Muscular Dystrophy, which in humans results from defects in muscle attachment.
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