A dozen questions about how tissue cells crawl

A series of long-standing questions about tissue cell locomotion now need to be reconsidered in relation to accumulating molecular information. For example, if ruffling represents localized re-assembly of actin at advancing cell margins, does this mean that contact inhibition of cell locomotion reflects inhibition of actin assembly at cell-cell contacts or adhesions? If so, then to what extent does invasiveness result from abnormal continuation of actin assembly at contacted margins? What mechanisms restrict actin assembly to certain parts of cells, margins, and how do microtubules control this, such that fibroblasts become less directional ('the Vasiliev phenomenon'), but more strongly contractile ('the Danowski phenomenon'), when treated with microtubule inhibitors? What concentrates cell-substratum adhesions into foci, and reduces adhesions beneath cell centres? A related question is whether actomyosin stress fibres are nucleated at focal adhesions, as opposed to being gathered together from lamellipodial actin; in addition, how are myosins added into the fibres in such a way as to contribute to force exertion? Does the orientation of fibroblasts along ridges result from inhibition of actin oriented across ridges, or from stimulation of actin assembly where cell margins are bent? Related questions concern the roles of cellular traction forces in embryonic development, whether cell sorting and aggregate rounding are due more to active contraction or to maximization of adhesion, and why individual cells round-up in mitosis or when treated with very high pressures or deprived of bivalent cations. Alternative answers to each question are discussed in relation to the available evidence.