Abstract
BackgroundIn the early stages of development of the cellular slime mold Dictyostelium discoideum, chemotaxis toward cAMP plays a pivotal role in organizing discrete cells into a multicellular structure. In this process, a series of signaling molecules, such as G-protein-coupled cell surface receptors for cAMP, phosphatidylinositol metabolites, and cyclic nucleotides, function as the signal transducers for controlling dynamics of cytoskeleton. Differentiation-inducing factor-1 and -2 (DIF-1 and DIF-2) were originally identified as the factors (chlorinated alkylphenones) that induce Dictyostelium stalk cell differentiation, but it remained unknown whether the DIFs had any other physiologic functions.Methodology/Principal FindingsTo further elucidate the functions of DIFs, in the present study we investigated their effects on chemotaxis under various conditions. Quite interestingly, in shallow cAMP gradients, DIF-1 suppressed chemotaxis whereas DIF-2 promoted it greatly. Analyses with various mutants revealed that DIF-1 may inhibit chemotaxis, at least in part, via GbpB (a phosphodiesterase) and a decrease in the intracellular cGMP concentration ([cGMP]i). DIF-2, by contrast, may enhance chemotaxis, at least in part, via RegA (another phosphodiesterase) and an increase in [cGMP]i. Using null mutants for DimA and DimB, the transcription factors that are required for DIF-dependent prestalk differentiation, we also showed that the mechanisms for the modulation of chemotaxis by DIFs differ from those for the induction of cell differentiation by DIFs, at least in part.Conclusions/SignificanceOur findings indicate that DIF-1 and DIF-2 function as negative and positive modulators for Dictyostelium chemotaxis, respectively. To our knowledge, this is the first report in any organism of physiologic modulators (small molecules) for chemotaxis having differentiation-inducing activity.
Highlights
Chemotaxis—a fundamental cellular function for sensing the direction of extracellular stimuli and migrating toward or away from the source—is involved in various biological and physiologic events, such as lymphocyte homing, angiogenesis, embryogenesis, wound healing, and some inflammatory disorders [1,2,3]
In Ax2 cells starved for 6–8 h, DIF-1 inhibited chemotaxis toward 0.1–1 nM cAMP, and DIF-2 promoted it greatly; despite their structural similarity (Fig. 1A), the DIFs showed opposite effects on chemotaxis
These results suggest that DIF-1 and DIF-2 function as modulators of chemotactic cell movement toward cAMP in Ax2 cells that have been starved for more than 6 h
Summary
Chemotaxis—a fundamental cellular function for sensing the direction of extracellular stimuli and migrating toward or away from the source—is involved in various biological and physiologic events, such as lymphocyte homing, angiogenesis, embryogenesis, wound healing, and some inflammatory disorders [1,2,3]. Dictyostelium discoideum is an excellent model organism for the analysis of both chemotaxis and cell differentiation. These vegetative amoebae grow by eating bacteria, and upon starvation, start morphogenesis. In the early stages of development of the cellular slime mold Dictyostelium discoideum, chemotaxis toward cAMP plays a pivotal role in organizing discrete cells into a multicellular structure. In this process, a series of signaling molecules, such as G-protein-coupled cell surface receptors for cAMP, phosphatidylinositol metabolites, and cyclic nucleotides, function as the signal transducers for controlling dynamics of cytoskeleton. Differentiation-inducing factor-1 and -2 (DIF-1 and DIF-2) were originally identified as the factors (chlorinated alkylphenones) that induce Dictyostelium stalk cell differentiation, but it remained unknown whether the DIFs had any other physiologic functions
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