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Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism.

ABSTRACT: Chemoattractants like fMet-Leu-Phe (fMLP) induce neutrophils to polarize with phosphatidylinositol 3,4,5-trisphosphate (PIP3) and protrusive F-actin at the front and actomyosin contraction at the sides and back. RhoA and its downstream effector, myosin II, mediate the "backness" response, which locally inhibits the "frontness" response and constrains its location to one part of the cell. In living HL-60 cells, we used a fluorescent PIP3 probe or a single-chain FRET biosensor for RhoA-GTP to assess spatial distribution of frontness or backness responses, respectively, during the first 3 min after exposure to a uniform concentration of fMLP. Increased PIP3 signal or RhoA activity initially localized randomly about the cell's periphery but progressively redistributed to the front or to the back and sides, respectively. Cells rendered unable to mount the frontness response (by inhibiting actin polymerization or Gi, a trimeric G protein) responded to a micropipette source of attractant by localizing RhoA activity at the up-gradient edge. We infer that protrusive F-actin, induced by the frontness response, constrains the spatial distribution of backness by locally reducing activation of RhoA, thereby reducing its active form at the front. Mutual incompatibility of frontness and backness is responsible for self-organization of neutrophil polarity.

SUBMITTER: Wong K

PROVIDER: S-EPMC1450135 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism.

Wong Kit K Pertz Olivier O Hahn Klaus K Bourne Henry H

Proceedings of the National Academy of Sciences of the United States of America 20060228 10

Chemoattractants like fMet-Leu-Phe (fMLP) induce neutrophils to polarize with phosphatidylinositol 3,4,5-trisphosphate (PIP3) and protrusive F-actin at the front and actomyosin contraction at the sides and back. RhoA and its downstream effector, myosin II, mediate the "backness" response, which locally inhibits the "frontness" response and constrains its location to one part of the cell. In living HL-60 cells, we used a fluorescent PIP3 probe or a single-chain FRET biosensor for RhoA-GTP to asse ...[more]

PMID: 16537448

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Project description:BackgroundA fundamental issue in bioscience is to understand the mechanism that underlies the dynamic control of genome-wide expression through the complex temporal-spatial self-organization of the genome to regulate the change in cell fate. We address this issue by elucidating a physically motivated mechanism of self-organization.Principal findingsBuilding upon transcriptome experimental data for seven distinct cell fates, including early embryonic development, we demonstrate that self-organized criticality (SOC) plays an essential role in the dynamic control of global gene expression regulation at both the population and single-cell levels. The novel findings are as follows: i) Mechanism of cell-fate changes: A sandpile-type critical transition self-organizes overall expression into a few transcription response domains (critical states). A cell-fate change occurs by means of a dissipative pulse-like global perturbation in self-organization through the erasure of initial-state critical behaviors (criticality). Most notably, the reprogramming of early embryo cells destroys the zygote SOC control to initiate self-organization in the new embryonal genome, which passes through a stochastic overall expression pattern. ii) Mechanism of perturbation of SOC controls: Global perturbations in self-organization involve the temporal regulation of critical states. Quantitative evaluation of this perturbation in terminal cell fates reveals that dynamic interactions between critical states determine the critical-state coherent regulation. The occurrence of a temporal change in criticality perturbs this between-states interaction, which directly affects the entire genomic system. Surprisingly, a sub-critical state, corresponding to an ensemble of genes that shows only marginal changes in expression and consequently are considered to be devoid of any interest, plays an essential role in generating a global perturbation in self-organization directed toward the cell-fate change.Conclusion and significance'Whole-genome' regulation of gene expression through self-regulatory SOC control complements gene-by-gene fine tuning and represents a still largely unexplored non-equilibrium statistical mechanism that is responsible for the massive reprogramming of genome expression.

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Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism.

Publications

Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism.

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