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Neutrophil microtubules suppress polarity and enhance directional migration.

ABSTRACT: How do microtubules, which maintain and direct polarity of many eukaryotic cells, regulate polarity of blood neutrophils? In sharp contrast to most cells, disrupting a neutrophil's microtubule network with nocodazole causes it to polarize and migrate [Niggli, V. (2003) J. Cell Sci. 116, 813-822]. Nocodazole induces the same responses in differentiated HL-60 cells, a model neutrophil cell line, and reduces their chemotactic prowess by causing them to pursue abnormally circuitous paths in migrating toward a stationary point source of an attractant, f-Met-Leu-Phe (fMLP). The chemotactic defect stems from dramatic nocodazole-induced imbalance between the divergent, opposed fMLP-induced "backness" and "frontness" signals responsible for neutrophil polarity. Nocodazole (i) stimulates backness by increasing Rho- and actomyosin-dependent contractility, as reported by Niggli, and also (ii) impairs fMLP-dependent frontness: pseudopods are flatter, contain less F-actin, and show decreased membrane translocation of PH-Akt-GFP, a fluorescent marker for 3'-phosphoinositide lipids. Inhibiting backness with a pharmacologic inhibitor of a Rho-dependent kinase substantially reverses nocodazole's effects on chemotaxis, straightness of migration paths, morphology, and PH-Akt-GFP translocation. Thus, microtubules normally balance backness vs. frontness signals, preventing backness from reducing the strength of pseudopods and from impairing directional migration.

SUBMITTER: Xu J

PROVIDER: S-EPMC1087512 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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Neutrophil microtubules suppress polarity and enhance directional migration.

Xu Jingsong J Wang Fei F Van Keymeulen Alexandra A Rentel Maike M Bourne Henry R HR

Proceedings of the National Academy of Sciences of the United States of America 20050428 19

How do microtubules, which maintain and direct polarity of many eukaryotic cells, regulate polarity of blood neutrophils? In sharp contrast to most cells, disrupting a neutrophil's microtubule network with nocodazole causes it to polarize and migrate [Niggli, V. (2003) J. Cell Sci. 116, 813-822]. Nocodazole induces the same responses in differentiated HL-60 cells, a model neutrophil cell line, and reduces their chemotactic prowess by causing them to pursue abnormally circuitous paths in migratin ...[more]

PMID: 15860582

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Project description:Inversin is a ciliary protein that critically regulates developmental processes and tissue homeostasis in vertebrates, partly through the degradation of Dishevelled (Dvl) proteins to coordinate Wnt signaling in planar cell polarity (PCP). Here, we investigated the role of Inversin in coordinating cell migration, which highly depends on polarity processes at the single-cell level, including the spatial and temporal organization of the cytoskeleton as well as expression and cellular localization of proteins in leading edge formation of migrating cells. Using cultures of mouse embryonic fibroblasts (MEFs) derived from inv(-/-) and inv(+/+) animals, we confirmed that both inv(-/-) and inv(+/+) MEFs form primary cilia, and that Inversin localizes to the primary cilium in inv(+/+) MEFs. In wound healing assays, inv(-/-) MEFs were severely compromised in their migratory ability and exhibited cytoskeletal rearrangements, including distorted lamellipodia formation and cilia orientation. Transcriptome analysis revealed dysregulation of Wnt signaling and of pathways regulating actin organization and focal adhesions in inv(-/-) MEFs as compared to inv(+/+) MEFs. Further, Dvl-1 and Dvl-3 localized to MEF primary cilia, and β-catenin/Wnt signaling was elevated in inv(-/-) MEFs, which moreover showed reduced ciliary localization of Dvl-3. Finally, inv(-/-) MEFs displayed dramatically altered activity and localization of RhoA, Rac1, and Cdc42 GTPases, and aberrant expression and targeting of the Na(+)/H(+) exchanger NHE1 and ezrin/radixin/moesin (ERM) proteins to the edge of cells facing the wound. Phosphorylation of β-catenin at the ciliary base and formation of well-defined lamellipodia with localization and activation of ERM to the leading edge of migrating cells were restored in inv(-/-) MEFs expressing Inv-GFP. Collectively, our findings point to the significance of Inversin in controlling cell migration processes, at least in part through transcriptional regulation of genes involved in Wnt signaling and pathways that control cytoskeletal organization and ion transport.

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Neutrophil microtubules suppress polarity and enhance directional migration.

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Neutrophil microtubules suppress polarity and enhance directional migration.

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