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Differentiation-inducing factor-1 and -2 function also as modulators for Dictyostelium chemotaxis.

Kuwayama H, Kubohara Y - PLoS ONE (2009)

Bottom Line: To further elucidate the functions of DIFs, in the present study we investigated their effects on chemotaxis under various conditions.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)).To our knowledge, this is the first report in any organism of physiologic modulators (small molecules) for chemotaxis having differentiation-inducing activity.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.

ABSTRACT

Background: 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.

Methodology/principal findings: To 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 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/significance: Our 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.

Show MeSH
(A) Model of signaling pathways leading to Dictyostelium chemotaxis.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 to control the dynamics of the cytoskeleton. DIFs modulate chemotaxis by affecting [cGMP]i. cAR1, G-protein-coupled cAMP receptor; PLA2, phospholipase A2; PLC, phospholipase C; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; DAG, diacylglycerol; IP3, inositol (1,4,5)-triphosphate; GCase, guanylyl cyclases. (B) Proposed model for how DIFs modulate Dictyostelium chemotaxis. DIF-1 inhibits chemotaxis, at least in part, via activation of GbpB and a subsequent decrease in [cGMP]i, whereas DIF-2 enhances chemotaxis, at least in part, via a RegA-dependent pathway and a subsequent increase in [cGMP]i. At high concentrations (e.g., 100 nM), DIF-1 and DIF-2 may cross-affect the other pathway to some extent; therefore, DIFs showed the same effects of inhibiting chemotaxis in regA- cells and of enhancing chemotaxis in gbpB- cells (Fig. 6A).
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pone-0006658-g007: (A) Model of signaling pathways leading to Dictyostelium chemotaxis.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 to control the dynamics of the cytoskeleton. DIFs modulate chemotaxis by affecting [cGMP]i. cAR1, G-protein-coupled cAMP receptor; PLA2, phospholipase A2; PLC, phospholipase C; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; DAG, diacylglycerol; IP3, inositol (1,4,5)-triphosphate; GCase, guanylyl cyclases. (B) Proposed model for how DIFs modulate Dictyostelium chemotaxis. DIF-1 inhibits chemotaxis, at least in part, via activation of GbpB and a subsequent decrease in [cGMP]i, whereas DIF-2 enhances chemotaxis, at least in part, via a RegA-dependent pathway and a subsequent increase in [cGMP]i. At high concentrations (e.g., 100 nM), DIF-1 and DIF-2 may cross-affect the other pathway to some extent; therefore, DIFs showed the same effects of inhibiting chemotaxis in regA- cells and of enhancing chemotaxis in gbpB- cells (Fig. 6A).

Mentions: Our results in mutants lacking the cyclic nucleotide phophodiesterase (PDE) genes regA and gbpB [26], [27] were particularly striking. To our surprise, DIFs at 100 nM showed the same effects of inhibiting chemotaxis in regA- cells and of enhancing chemotaxis in gbpB- cells (Fig. 6A). In clear contrast, however, in regA- cells, DIF-1 at 10 nM inhibited chemotaxis but DIF-2 at 10 nM did not affect chemotaxis (Fig. 6B), whereas in gbpB- cells, DIF-2 at 10 nM enhanced chemotaxis but DIF-1 at 10 nM did not affect chemotaxis (Fig. 6B). These results strongly suggest that the pathways by which DIF-1 and DIF-2 modulate chemotaxis involve GbpB (PDE for cGMP) [27] and RegA (PDE for cAMP?) [28], respectively, and that DIF-1 and DIF-2 at high concentrations (e.g., 100 nM) may have the potential to cross-affect the other pathway (Fig. 7B). More precisely, DIF-1 may inhibit chemotaxis, at least in part, via GbpB activation and a subsequent decrease in the intracellular cGMP concentration ([cGMP]i), whereas DIF-2 may enhance chemotaxis, at least in part, via a RegA-dependent pathway.


Differentiation-inducing factor-1 and -2 function also as modulators for Dictyostelium chemotaxis.

Kuwayama H, Kubohara Y - PLoS ONE (2009)

(A) Model of signaling pathways leading to Dictyostelium chemotaxis.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 to control the dynamics of the cytoskeleton. DIFs modulate chemotaxis by affecting [cGMP]i. cAR1, G-protein-coupled cAMP receptor; PLA2, phospholipase A2; PLC, phospholipase C; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; DAG, diacylglycerol; IP3, inositol (1,4,5)-triphosphate; GCase, guanylyl cyclases. (B) Proposed model for how DIFs modulate Dictyostelium chemotaxis. DIF-1 inhibits chemotaxis, at least in part, via activation of GbpB and a subsequent decrease in [cGMP]i, whereas DIF-2 enhances chemotaxis, at least in part, via a RegA-dependent pathway and a subsequent increase in [cGMP]i. At high concentrations (e.g., 100 nM), DIF-1 and DIF-2 may cross-affect the other pathway to some extent; therefore, DIFs showed the same effects of inhibiting chemotaxis in regA- cells and of enhancing chemotaxis in gbpB- cells (Fig. 6A).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2722026&req=5

pone-0006658-g007: (A) Model of signaling pathways leading to Dictyostelium chemotaxis.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 to control the dynamics of the cytoskeleton. DIFs modulate chemotaxis by affecting [cGMP]i. cAR1, G-protein-coupled cAMP receptor; PLA2, phospholipase A2; PLC, phospholipase C; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; DAG, diacylglycerol; IP3, inositol (1,4,5)-triphosphate; GCase, guanylyl cyclases. (B) Proposed model for how DIFs modulate Dictyostelium chemotaxis. DIF-1 inhibits chemotaxis, at least in part, via activation of GbpB and a subsequent decrease in [cGMP]i, whereas DIF-2 enhances chemotaxis, at least in part, via a RegA-dependent pathway and a subsequent increase in [cGMP]i. At high concentrations (e.g., 100 nM), DIF-1 and DIF-2 may cross-affect the other pathway to some extent; therefore, DIFs showed the same effects of inhibiting chemotaxis in regA- cells and of enhancing chemotaxis in gbpB- cells (Fig. 6A).
Mentions: Our results in mutants lacking the cyclic nucleotide phophodiesterase (PDE) genes regA and gbpB [26], [27] were particularly striking. To our surprise, DIFs at 100 nM showed the same effects of inhibiting chemotaxis in regA- cells and of enhancing chemotaxis in gbpB- cells (Fig. 6A). In clear contrast, however, in regA- cells, DIF-1 at 10 nM inhibited chemotaxis but DIF-2 at 10 nM did not affect chemotaxis (Fig. 6B), whereas in gbpB- cells, DIF-2 at 10 nM enhanced chemotaxis but DIF-1 at 10 nM did not affect chemotaxis (Fig. 6B). These results strongly suggest that the pathways by which DIF-1 and DIF-2 modulate chemotaxis involve GbpB (PDE for cGMP) [27] and RegA (PDE for cAMP?) [28], respectively, and that DIF-1 and DIF-2 at high concentrations (e.g., 100 nM) may have the potential to cross-affect the other pathway (Fig. 7B). More precisely, DIF-1 may inhibit chemotaxis, at least in part, via GbpB activation and a subsequent decrease in the intracellular cGMP concentration ([cGMP]i), whereas DIF-2 may enhance chemotaxis, at least in part, via a RegA-dependent pathway.

Bottom Line: To further elucidate the functions of DIFs, in the present study we investigated their effects on chemotaxis under various conditions.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)).To our knowledge, this is the first report in any organism of physiologic modulators (small molecules) for chemotaxis having differentiation-inducing activity.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.

ABSTRACT

Background: 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.

Methodology/principal findings: To 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 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/significance: Our 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.

Show MeSH