The events studied in Projects 1 and 2 are essential prerequisites for the actual movement of cells towards the source of cAMP. Translocation of the cells allows them to aggregate into groups of up to 105 cells and proceed through multicellular development. Cell movement is an essential process in many multicellular organisms. In vertebrates it plays essential roles in embryogenesis, organogenesis, wound healing and, when aberrant, can lead to birth defects and cancer metastasis (Baggiolini, 1998;Behar et al., 1994;Clark, 1996; Condeelis et al., 2005;Dormann and Weijer, 2003;Muller et al., 2001). Dictyostelium cells are highly motile even while growing as they search for food. The rate of cell movement increases to a peak during the aggregation stage when they signal each other with periodic pulses of cAMP. We have recently shown that a molecular circuit involving the cAMP receptor, adenylyl cyclase, cAMP phosphodiesterase, MAP kinase and PKA generates spontaneous oscillations in cAMP synthesis (Laub and Loomis, 1998). We also have evidence that many of these components are essential for chemotaxis in a natural wave (Maeda et al., 2004;Stepanovic et al., 2005;Wessels et al., 2004;Zhang et al., 2003). Our working hypothesis is that the circuit is coupled to cell movement such that signaling and response are always in phase (Loomis, 2007). Dictyostelium cells provide an excellent test system to further understand the basic biology of cell motility, which appears to have been conserved during evolution leading to vertebrates. In Project 3, we will focus on several aspects of the chemotactic response to temporal and spatial aspects of cAMP waves that leads to aggregation. We will be able to benefit from the expertise we have developed in controlling the cAMP environment within microfluidic devises and the computer assisted quantification of instantaneous velocity of a large number of cells.
Three specific aims will be addressed in Project 3.
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