The dynamic nature of the actin cytoskeleton requires the continual nucleation of new filaments or new filament branches. Extension of these newly formed branches occurs at the interface between the leading edge and the existing actin filament network [1] and is maintained by mechanisms such as actin treadmilling. As reviewed in [1] a number of models propose mechanisms by which actin filament dynamics lead to the generation of protrusive force, and subsequently lamellipodia extension. Early models, including the ‘Brownian ratchet’ theory [2] and the ‘Elastic ratchet’ theory [3], considered the process from a molecular level where each actin filament acted independently of others. Extending filaments would push against the membrane, and in the process a gap, produced either by membrane resistance or by the thermal wave like properties of an elastic non-rigid filament, would allow for the addition of G-actin onto the barbed end of extending filaments.

Although these models could account for the generation of protrusive force, they did not consider actin polymerization from an in vivo perspective where its dynamics are influenced by an array of factors. Direct interactions between growing actin filaments and the membrane were addressed in later models such as the ‘tethered ratchet’ model [4] where filaments were proposed to attach transiently to the membrane and protrusive force was generated by the addition of G-actin onto compressed filaments which had temporarily dissociated from the membrane. Similarly the influence of surface curvature was considered in the ‘elastic propulsion’ model [5] whilst the role of the greater filament network on filament polymerization was considered in the ‘autocatalytic branching’ theory [6].

With the specific factors that mediate force generation from F-actin assembly still to be defined, models such as those mentioned above will continue to be developed and built upon. It is clear however that actin treadmilling is integral to each model, being essential to both F-actin assembly and lamellipodia growth.

Lamellipodia Extension

Filament extension occurs via the ‘actin treadmilling’ mechanism, with lamellipodial growth reflecting the balance between actin filament polymerization at the barbed ends and retrograde actin flow towards the cell body (reviewed in [3]). Motile cells adjust the rate of actin assembly in specific regions of the cell to outpace retrograde flow, thereby favoring cell contact and protrusion in a particular direction [4]. In certain motile cells (e.g. fish keratocytes), the actin cytoskeleton remains stationary relative to the substratum, indicating that there is virtually no retrograde actin flow and therefore the rate of actin polymerization equals the rate of protrusion [5].

Lamellipodial extension is often coupled to larger events that facilitate cell motility and mechanosensing. For example, extension of the actin filament network is essential in periodic contractions. This process, is primarily driven by myosin motor proteins (see ‘Functional Module: Myosin II in Filament Retraction’) and allows the cell to sense and measure the rigidity of its surroundings. Myosin motors localize behind the actin filament network, making filament extension essential to facilitate the rearward movement of older filaments towards these motors – a process resulting from the retrograde movement that occurs during filament extension.

Along with periodic contractions, lamellipodial extension may also occur along with peripheral membrane ruffling or with circular dorsal ruffles.

Pause and Stasis Although the lamellipodial actin network is highly dynamic, moments of pause and stasis have been reported [6]. This has been correlated to the angle of actin filaments at the membrane interface, with a greater number of ‘low angle’ filaments being seen to align in parallel to the leading edge during longer pauses [6]. These ‘low angle’ filaments continue to extend whilst shorter ‘high angle’ filaments depolymerize, resulting in a net reduction in protrusion [6]. Pause and stasis also allow time for maturation and elongation of nascent focal adhesions along the actin network [7]. This has been shown to occur particularly at the interface of lamellipodia and lamellae [7].