Control of cell migration through mRNA localization and local translation

Abstract

Cell migration plays an important role in many normal and pathological functions such as development, wound healing, immune defense, and tumor metastasis. Polarized migrating cells exhibit asymmetric distribution of many cytoskeletal proteins, which is believed to be critical for establishing and maintaining cell polarity and directional cell migration. To target these proteins to the site of function, cells use a variety of mechanisms such as protein transport and messenger RNA (mRNA) localization-mediated local protein synthesis. In contrast to the former which is intensively investigated and relatively well understood, the latter has been understudied and relatively poorly understood. However, recent advances in the study of mRNA localization and local translation have demonstrated that mRNA localization and local translation are specific and effective ways for protein localization and are crucial for embryo development, neuronal function, and many other cellular processes. There are excellent reviews on mRNA localization, transport, and translation during development and other cellular processes. This review will focus on mRNA localization-mediated local protein biogenesis and its impact on somatic cell migration.

Figure 1. Arp3 protein and mRNA are localized at the cell leading protrusions in wound tissue

Day 4 rat skin wound tissue cryo-sections were processed for protein using immunofluorescence staining (A) or for mRNA using fluorescence in situ hybridization with tyramide signal amplification (B). To present a whole 10 µm cryo-section, 10 digital images of optical Z-sections (1 µm each) were deconvolved to remove out-focus fluorescence and then compressed to generate a 2-D projection image. Note in A that the stationary keratinocytes over the wound bed (above the dotted line) exhibit a relatively uniform distribution of Arp3 protein. The Arp2/3 is a very stable protein complex, and detection of one member is indicative of the location of this protein complex. Arrows point to the localized protein (red in A) and arrowheads point to localized mRNA (green in B). Unpublished data of Mingle, Van De Water and Liu.

Figure 2. Visualization of Arp2 mRNA movement in live fibroblasts

A. Illustration of the MS2 system for visualization of RNA in live cells (model adapted from Bertrand et al.). The phage MS2 coat protein (MCP) is fused with GFP, and a nuclear localization signal (NLS) tag that sequesters the MCP-GFP in the nucleus if it is not bound to the mRNA. The MS2 stem-loop repeat is inserted into the 3-UTR of Arp2 mRNA. The MCP-GFP protein binds to the MS2 RNA repeat with high affinity so the location of the mRNA can be detected by the GFP fluorescence. B. Still images from a one-hour time lapse show the dynamic movement of the Arp2 mRNA in a fibroblast cell. Arrows point to the protrusions and arrowheads point to the nucleus in which the unbound MCP-GFP is sequestered. Unpublished data of Mingle and Liu.

Figure 3. Differential intracellular distribution of the Arp2/3 mRNA and Dia1 mRNA in fibroblasts

Representative intracellular distribution of Arp2 mRNA (green) and Dia1 mRNA (red) in the CEFs. Dash lines indicate cell border and blue for nucleus. Arp2 mRNA (green) is concentrated at the leading lamella while the Dia1 mRNA (red) is perinuclear. Similar differential distribution of the Arp2/3 complex mRNAs and Dia1 mRNA were also observed in human foreskin fibroblasts (not shown). Adapted from.