Cell shape regulation through mechanosensory feedback control

Abstract

Cells undergo controlled changes in morphology in response to intracellular and extracellular signals. These changes require a means for sensing and interpreting the signalling cues, for generating the forces that act on the cell's physical material, and a control system to regulate this process. Experiments on Dictyostelium amoebae have shown that force-generating proteins can localize in response to external mechanical perturbations. This mechanosensing, and the ensuing mechanical feedback, plays an important role in minimizing the effect of mechanical disturbances in the course of changes in cell shape, especially during cell division, and likely in other contexts, such as during three-dimensional migration. Owing to the complexity of the feedback system, which couples mechanical and biochemical signals involved in shape regulation, theoretical approaches can guide further investigation by providing insights that are difficult to decipher experimentally. Here, we present a computational model that explains the different mechanosensory and mechanoresponsive behaviours observed in Dictyostelium cells. The model features a multiscale description of myosin II bipolar thick filament assembly that includes cooperative and force-dependent myosinactin binding, and identifies the feedback mechanisms hidden in the observed mechanoresponsive behaviours of Dictyostelium cells during micropipette aspiration experiments. These feedbacks provide a mechanistic explanation of cellular retraction and hence cell shape regulation.

Mechanochemical Signaling Directs Cell-Shape Change

“…However, the ability of a long lever-arm mutant myosin (2xELC) in the context of the phosphomimic (3xAsp) tail mutant to assemble into filaments in vivo is highly consistent with the concept of cross talk between the two parts of the myosin molecule (60). Also, molecular simulations that accurately depict the behavior of nonmuscle myosin II in response to an applied stress require not just force feedback but also strained and unstrained states of myosin II bipolar filaments (in the strained state, the myosin remains assembled until the bipolar filament relaxes) (47). Thus, it is important to determine whether there is compliance in the nonmuscle myosin II tail, and how this compliance affects its mechanosensitive assembly and phosphoregulation.…”

“…2). Thus, the cleavage furrow cortex comprises a mechanochemical feedback loop where both chemical and mechanical signals promote accumulation of the appropriate machinery (46,47). This system is inherently quite robust: the network of cytokinesis cytoskeletal machinery stabilizes under mechanical load in a manner that is independent of any single protein (22).…”

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

“…The network stress-dependent stalling of myosin II heads in the strongly-bound state during the myosin power stroke gives rise to this cooperativity and promotes bipolar thick filament assembly [ 9 , 13, 18, 26]. Once the accumulated myosin II fully opposes the applied stress, the bound heads do not experience increasing stress, resulting in maximal accumulation [13,25].…”

“…2A,C). This biphasic behavior is characteristic of cooperative binding interactions, a behavior we previously modeled for Dictyostelium myosin II [ 25 ]. The network stress-dependent stalling of myosin II heads in the strongly-bound state during the myosin power stroke gives rise to this cooperativity and promotes bipolar thick filament assembly [ 9 , 13, 18, 26].…”

“…The network stress-dependent stalling of myosin II heads in the strongly-bound state during the myosin power stroke gives rise to this cooperativity and promotes bipolar thick filament assembly [ 9 , 13, 18, 26]. Once the accumulated myosin II fully opposes the applied stress, the bound heads do not experience increasing stress, resulting in maximal accumulation [13,25].Interestingly, while the accumulation kinetics for myosin IIA and IIC were nearly identical between cell types, myosin IIB showed highly cell-type and cell-cycle-stage specific behavior. In Jurkats, myosin IIB was the most mechanoresponsive paralog, achieving greater than two-fold normalized intensity relative to the opposite cortex.…”