The mDial formin is required for neutrophil polarization, migration, and activation of the LARG/RhoA/ROCK signaling axis during chemotaxis.
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.
Shi
Yongquan
Y
Department of Medicine, Samuel Lunenfeld and Toronto Hospital Research Institutes, University of Toronto, Toronto, Canada.
Zhang
Jinyi
J
Mullin
Michael
M
Dong
Baoxia
B
Alberts
Arthur S
AS
Siminovitch
Katherine A
KA
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D025461:Feedback, Physiological / Q000276:immunology; D005326:Fetal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000080865:Formins; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D054460:rho-Associated Kinases / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
C577223:Arhgef12 protein, mouse; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D005326:Fetal Proteins; D000080865:Formins; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein