Although previously unappreciated, it now seems obvious that actin-driven cell motility requires genomic support. Several independent mechanisms can now be outlined that communicate the dynamic status of the actin cytoskeleton to the genome. Microfilament-to-genome communication is mediated by different courier proteins, representing G-ABPs, F-ABPs or F-ACAPs, the cytoplasmic release of which for nuclear translocation is dependent on changes in G-actin levels or F-actin structure and composition. Such courier proteins can function inside nuclei as transcriptional cofactors, as clearly shown for the CRP, FHL2, JMy and MRTF proteins. The control of SRF activity by multiple cofactor interactions and signalling inputs serves as a paradigm for understanding the logic of connecting genome activity with actin cytoskeletal dynamics. The intimate functional link between actin dynamics, MRTF–SRF-regulated gene expression and cellular motile behaviour has been confirmed by genetic means in several cell and organ systems, including embryonic stem cells48
, the developing mouse embryo73,116,137
, muscle tissues82,138
and the brain11,139,140
. However, numerous molecular details of the regulatory interactions involved remain to be worked out in the MRTF–SRF circuit and in all the other above-mentioned systems.
We anticipate that new actin-dependent courier proteins will be identified. For each relay system it will be important to characterize comprehensively the associated differential gene expression profiles. The example of MRTF–SRF-directed expression of miRnA-encoding genes indicates that surprising mechanistic insight is to be derived from future studies in this area of cell biology.
Microbial pathogens, both bacteria (for example, Listeria
Spp. and enteropathogenic Escherichia coli
) and viruses (for example, vaccinia virus), subvert actin cytoskeletal functions of the infected host cell by modulating its actin dynamics (for review see REF. 141
). it is likely that these influences on micro filament remodelling are accompanied by changes in gene activity and we postulate that this involves the MRTF–SRF circuit. It is equally possible that other, hitherto undetected, G-ABPs might be involved in such events of host cell infection. In more general terms, actin dynamics might communicate to the genome and thereby combat other cellular insults, as already seen in the context of UV-induced DNA damage.
Vesicle trafficking such as endocytosis, exocytosis and Golgi-to-endoplasmic reticulum transport, which are dependent on dynamic actin rearrangements, might also elicit and even require changes in gene expression. This poorly studied aspect of membrane trafficking warrants closer investigation and may offer surprising new insights.
Embryonic development requires cell movement and motile functions at many essential steps. The precise contributions of microfilament-to-genome communication to these activities are still inadequately understood. Although participation of SRF in mouse gastrulation was noticed early on73
, the MRTF–SRF circuit is expected to contribute to development in many additional ways, including enabling functions during EMT22
and stem cell programming and reprogramming117
. Deeper insight into these issues will prove rewarding.
The remarkable progress in identifying actin-dependent SRF cofactors and determining their mechanisms of action has provided new insights into the myriad aspects of cell physiology, development and disease. Given the likely involvement of the actin–MRTF–SRF pathway in tissue remodelling during disease, it will be important to determine how this and similar pathways of cytoskeleton-to-nucleus communication can be therapeutically modulated.