The long-term goal of the proposed research is to learn how to cell-cell communication can control the positioning of cells in developing organisms. This study will focus on the migration of a pair of sex myoblasts (SMs) in Caenorhabditis. elegans hermaphrodites that is controlled by a signal that attracts the SMs to their precise final positions. The mechanisms by which this signaling system ultimately alters the movements of the SMs will be investigated by molecularly characterizing four genes with known roles in this process and genetically identify additional components. Several aspects of this system make it uniquely suited for analyzing how signals guide migrating cells: 91) the migrating cell is attracted by a signal whose source is known; (2) components of the system have already been identified; (3) additional components can be identified by simple genetic screens; and (4) standard molecular and genetic techniques can be used to characterize these components. The four known key genes to be studied are: (1)sem-5, a gene involved in multiple signaling processes that encodes a protein with SH2 and SH3 (src homology) domains, hallmarks of many proteins with known roles in signal transduction; (2 & 3) egl-12 and egl-17, in which mutations can dramatically alter the migrations of the SMs; and (4) clr-1, a gene that regulates egl-15 and sem-5. These genes are part of a network of interacting genes that control signaling process in C. elegans. Other genes in this network encoded homologous of the ras and raf oncogenes and the epidermal growth factor receptor, which, when activated in mammalian systems, can lead to oncogenesis. Thus, these studies are directly relevant to our understanding of oncogenesis. There may also be clinically important ramifications if the deregulation of similar components in mammals leads to metastatic tumor progression.
The specific aims of this proposal are:(1) to continue the molecular characterization of the four key genes: egl-15, egl-17, sem-5 and clr-1; (2) to determine the sites of expression (by antibody staining) and action (by mosaic analysis) of these four gene; and (3) to identify genetically and characterize additional genes involved in cell-cell communications that guide migrating cells communications that guide migrating cells. The genetic and molecular characterizations proposed will define the relationships among these genes and begin to assign biochemical functions so as to understand their interactions at the molecular level. In this manner, we hope to learn how signals can guide migrating cells.

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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Yale University
Schools of Medicine
New Haven
United States
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