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The mDial Formin Is Required for Neutrophil Polarization, Migration, and Activation of the LARG/RhoA/ROCK Signaling Axis during Chemotaxis¹

Yongquan Shi^2,*, Jinyi Zhang^*,2, Michael Mullin^*, Baoxia Dong^*, Arthur S. Alberts and Katherine A. Siminovitch^3,*

^* Department of Medicine, University of Toronto, Samuel Lunenfeld and Toronto Hospital Research Institutes, Toronto, Canada; and Cell Structure and Signal Integration Laboratory, Van Andel Institute, Grand Rapids, MI 49503

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Canadian Institutes for Health Research (MOP12136) and the Leukemia and Lymphoma Society (to K.A.S.). K.A.S. is a McLaughlin Centre for Molecular Medicine Scientist and holds a Canada Research Chair in Immunogenomics.

² These authors contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Katherine Siminovitch, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 778D, Toronto, Ontario, M5G 1X5 Canada. E-mail address: ksimin{at}mshri.on.ca

⁴ Abbreviations used in this paper: ROCK, p160-Rho-associated coil-containing protein kinase; GBD, GTPase-binding domain; GEF, guanine nucleotide exchange factor; LARG, leukemia-associated Rho-GEF; mDia, mammalian diaphanous-related formin; MLC, myosin light chain; WASp, Wiskott-Aldrich syndrome protein; pMLC, phosphorylated MLC; LPA, lysophosphatidic; DIC, differential interference contrast.

⁵ The online version of this article contains supplemental material.