? Directional cell migration is a critical aspect of successful wound healing. Soon after injury, cells move into the wound bed and play key roles in tissue remodeling. Extensive studies have provided valuable information about how the extracellular matrix environment changes and """"""""pre-conditions"""""""" fibroblasts migrating into the wound bed. However, it is poorly understood how the intracellular mechanisms regulate the cells migrating directionally to the wound bed. To move directionally, a cell must become asymmetric and establish a dominant leading protrusion in which localized actin polymerization is a hallmark. The Arp2/3 complex, an actin polymerization nucleator consisting of seven proteins, is localized to the leading lamella in cultured cells. We have demonstrated that the Arp2/3 complex is localized in cells in culture and in healing wounds. The localization of the Arp2/3 protein complex is consistent with its function to promote formation of highly branched actin network for protrusion. However, it is unknown how the Arp2/3 protein complex is targeted in migrating cells. We have demonstrated that mRNAs for all the seven subunits of the Arp2/3 complex are localized at cell leading protrusion. This is the first evidence that mRNAs for a protein complex are co-localized to a common site of function. Because asymmetric distribution of mRNA is an important mechanism to target protein to the site of function through localized protein synthesis, this finding suggests that the Arp2/3 protein complex is targeted to the leading protrusion by mRNA localization. We hypothesize that Arp2/3 mRNA localization is a mechanism to target the Arp2/3 protein to the leading protrusion thereby governing directional cell migration. To test this hypothesis, we will identify the mRNA localization signaling sequence (the zipcode) in Arp2 (a key member of the complex). We will use three different approaches to disrupt the localization of Arp2 mRNA : 1) using antisense oligonucleotides to block the zipcode; 2) creating Arp2 mRNA chimera with non-localizing 3'-UTR; and 3) genetically mutating or deleting the zipcode. To test the importance of Arp2/3 localization in directional cell migration in vitro and in vivo, we will study the impact of delocalizing Arp2 mRNA on fibroblast migration behavior in tissue culture and in healing wounds. By elucidating the fundamental mechanisms with which cells regulate their directional motility, our experiments will provide a new basis for therapies to modulate cell migration in pathogenic settings such as fibrosis and tumor metastasis. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Ikeda, Richard A
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Albany Medical College
Anatomy/Cell Biology
Schools of Medicine
United States
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Liao, Guoning; Mingle, Lisa; Van De Water, Livingston et al. (2015) Control of cell migration through mRNA localization and local translation. Wiley Interdiscip Rev RNA 6:1-15
Liao, Guoning; Liu, Gang (2013) Immediate translation of Formin DIAPH1 mRNA after its exiting the nucleus is required for its perinuclear localization in fibroblasts. PLoS One 8:e68190
Liao, Guoning; Ma, Xinghong; Liu, Gang (2011) An RNA-zipcode-independent mechanism that localizes Dia1 mRNA to the perinuclear ER through interactions between Dia1 nascent peptide and Rho-GTP. J Cell Sci 124:589-99
Liao, Guoning; Simone, Brittany; Liu, Gang (2011) Mis-localization of Arp2 mRNA impairs persistence of directional cell migration. Exp Cell Res 317:812-22
Mingle, Lisa A; Bonamy, Ghislain; Barroso, Margarida et al. (2009) LPA-induced mutually exclusive subcellular localization of active RhoA and Arp2 mRNA revealed by sequential FRET and FISH. Histochem Cell Biol 132:47-58
Liu, G; Amin, S; Okuhama, N N et al. (2006) A quantitative evaluation of peroxidase inhibitors for tyramide signal amplification mediated cytochemistry and histochemistry. Histochem Cell Biol 126:283-91
Mingle, Lisa A; Okuhama, Nataly N; Shi, Jian et al. (2005) Localization of all seven messenger RNAs for the actin-polymerization nucleator Arp2/3 complex in the protrusions of fibroblasts. J Cell Sci 118:2425-33