Cell migration events play crucial roles in normal development, and aberrant migratory behavior, such as the migrations of metastatic cancer cells, can cause life-threatening diseases. Thus, a detailed understanding of the mechanisms that control the movement of cells is important both for our general understand of development as well as for providing targets for therapeutic reagents to combat metastatic cancer progression. Cell migration requires the interplay of the migration cell with the guidance causes and substrates which influence its movement. The long- range objective of this proposal is to understand the molecular basis for how migration cells read the extracellular cues that influence their migrations and integrate this information to result in directed cell movement. This proposal seeks to obtain a comprehensive understanding for the mechanisms guiding the migrations of the sex myoblasts (SMs) in the nematode Caenorhabditis elegans to attain this goal. The SMs in C. elegans hermaphrodites migrate anteriorly to final positions that flank the center of the developing gonad. The migrations of the SMs are known to be guided by a gonad-dependent attractive cue that appears to be a fibroblast growth factor (EGL-17) and a gonad-independent mechanism that requires the function of three genes, unc-53, unc-71, and unc-73. In the absence of the gonad-dependent attraction, the SMs are kept posterior by a gonad-dependent repulsion. In males, a similar set of SMs migrate posteriorly, although the components that directly regulate the sexually- dimorphic migrations of the SMs are not known. To accomplish our long-term objective, this proposal has the following specific aims: (1) Analyze the extend of involvement of the EGL-15 FGF receptor in the various SM migration mechanisms and determine whether it acts within the SMs by mosaic analysis. (2) Investigate whether EGL-17(FGF) emanates from the gonad to attract the SMs to their final positions. (3) Develop tissue-specific promoters to help probe the roles and sites of action of SM migration components. (4) Analyze the molecular basis of the gonad-independent mechanism by molecularly characterizing unc-71 and studying mutants that affect the gonad-independent sexually dimorphic direction of SM migration. (5) Identify components of the repelling to probe its role in normal SM migration guidance. Using these approaches, we hope to gain a better understanding of how the multiple mechanisms that influence the SMs cooperate to ensure reproducible precisely targeted migrations.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics Study Section (GEN)
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Greenberg, Judith H
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Yale University
Schools of Medicine
New Haven
United States
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