Abstract
Neutrophil chemotaxis depends on actin dynamics, but the roles for specific cytoskeleton regulators in this response remain unclear. By analysis of mammalian diaphanous-related formin 1 (mDia1)-deficient mice, we have identified an essential role for this actin nucleator in neutrophil chemotaxis. Lack of mDia1 was associated with defects in chemoattractant-induced neutrophil actin polymerization, polarization, and directional migration, and also with impaired activation of RhoA, its downstream target p160-Rho-associated coil-containing protein kinase (ROCK), and the leukemia-associated RhoA guanine nucleotide exchange factor (LARG). Our data also revealed mDia1 to be associated with another cytoskeletal regulator, Wiskott-Aldrich syndrome protein (WASp), at the leading edge of chemotaxing neutrophils and revealed polarized morphology and chemotaxis to be more mildly impaired in WAS(-/-) than in mDia1(-/-) neutrophils, but essentially abrogated by combined mDia1/WASp deficiency. Thus, mDia1 roles in neutrophil chemotaxis appear to be subserved in concert with WASp and are realized at least in part by activation of the LARG/RhoA/ROCK signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Movement / immunology
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Cell Polarity / immunology*
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Chemotaxis, Leukocyte / immunology*
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Feedback, Physiological / immunology
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Fetal Proteins / deficiency
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Fetal Proteins / genetics
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Fetal Proteins / physiology
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Formins
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Guanine Nucleotide Exchange Factors / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microfilament Proteins / deficiency
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Microfilament Proteins / genetics
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Microfilament Proteins / physiology
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Neutrophils / cytology
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Neutrophils / immunology*
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Neutrophils / metabolism
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology
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Rho Guanine Nucleotide Exchange Factors
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Signal Transduction / immunology*
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Wiskott-Aldrich Syndrome Protein / physiology
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rho GTP-Binding Proteins / physiology*
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rho-Associated Kinases / physiology*
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rhoA GTP-Binding Protein
Substances
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Arhgef12 protein, mouse
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Carrier Proteins
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Diap1 protein, mouse
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Fetal Proteins
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Formins
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Guanine Nucleotide Exchange Factors
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Microfilament Proteins
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Nuclear Proteins
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Rho Guanine Nucleotide Exchange Factors
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Was protein, mouse
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Wiskott-Aldrich Syndrome Protein
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Rock1 protein, mouse
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rho-Associated Kinases
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RhoA protein, mouse
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein