Autonomous epithelial folding induced by an intracellular mechano–polarity feedback loop

Epithelial tissues form folded structures during embryonic development and organogenesis. Whereas substantial efforts have been devoted to identifying mechanical and biochemical mechanisms that induce folding, whether and how their interplay synergistically shapes epithelial folds remains poorly understood. Here we propose a mechano–biochemical model for dorsal fold formation in the early Drosophila embryo, an epithelial folding event induced by shifts of cell polarity. Based on experimentally observed apical domain homeostasis, we couple cell mechanics to polarity and find that mechanical changes following the initial polarity shifts alter cell geometry, which in turn influences the reaction-diffusion of polarity proteins, thus forming a feedback loop between cell mechanics and polarity. This model can induce spontaneous fold formation in silico, recapitulate polarity and shape changes observed in vivo, and confer robustness to tissue shape change against small fluctuations in mechanics and polarity. These findings reveal emergent properties of a developing epithelium under control of intracellular mechano–polarity coupling.

Collective chemotaxis in a Voronoi model for confluent clusters

Collective chemotaxis, where single cells cannot climb a biochemical signaling gradient but clusters of cells can, has been observed in different biological contexts, including confluent tissues where there are no gaps or overlaps between cells. Although particle-based models have been developed that predict important features of collective chemotaxis, the mechanisms in those models depend on particle overlaps, and so it remains unclear if they can explain behavior in confluent systems. Here, we develop an open-source code that couples a 2D Voronoi simulation for confluent cell mechanics to a dynamic chemical signal that can diffuse, advect, and/or degrade, and use the code to study potential mechanisms for collective chemotaxis in cellular monolayers. We first study the impact of advection on collective chemotaxis, and delineate a regime where advective terms are important. Next, we investigate two possible chemotactic mechanisms, contact inhibition of locomotion and heterotypic interfacial tension, and demonstrate that both can drive collective chemotaxis in certain parameter regimes. We further demonstrate that the scaling behavior of cluster motion is well-captured by simple analytic theories.

Spontaneous rotations in epithelia as an interplay between cell polarity and RhoA activity at boundaries.

Directed flows of cells in vivo are essential in morphogenesis. They shape living matter in phenomena involving cell mechanics and regulations of the acto-myosin cytoskeleton. However the onset of coherent motion during collective cell migration is still poorly understood. Here we show that coherence is set by spontaneous alignments of cell polarity by designing cellular rings of controlled dimensions. A tug-of-war between opposite polarities dictates the onset of coherence, as assessed by tracking live cellular shapes and motions in various experimental conditions. In addition, we identify an internally driven constraint by cellular acto-myosin cables at boundaries as essential to ensure coherence and active force is generated as evaluated by the high RhoA activity. Its contribution is required to trigger coherence as shown by our numerical simulations based on a novel Vicsek-type model including free active boundaries. Altogether, spontaneous coherent motion results from basic interplay between cell orientations and active cables at boundaries.

Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly

Malignancy is associated with changes in cell mechanics that contribute to extensive cell deformation required for metastatic dissemination. We hypothesized that the cell-intrinsic physical factors that maintain epithelial cell mechanics could function as tumor suppressors. Here we show, using optical tweezers, genetic interference, mechanical perturbations, and in vivo studies, that epithelial cells maintain higher plasma membrane (PM) tension than their metastatic counterparts and that high PM tension potently inhibits cancer cell migration and invasion by counteracting membrane curvature sensing/generating BAR family proteins. This tensional homeostasis is achieved by membrane-to-cortex attachment (MCA) regulated by ERM proteins, whose disruption spontaneously transforms epithelial cells into a mesenchymal migratory phenotype powered by BAR proteins. Consistently, the forced expression of epithelial–mesenchymal transition (EMT)-inducing transcription factors results in decreased PM tension. In metastatic cells, increasing PM tension by manipulating MCA is sufficient to suppress both mesenchymal and amoeboid 3D migration, tumor invasion, and metastasis by compromising membrane-mediated mechanosignaling by BAR proteins, thereby uncovering a previously undescribed mechanical tumor suppressor mechanism.

Partitioning of ribonucleoprotein complexes from the cellular actin cortex

The cell cortex plays a crucial role in cell mechanics, signaling, and development. However, little is known about the influence of the cortical meshwork on the spatial distribution of cytoplasmic biomolecules. Here, we describe a new fluorescence microscopy method to infer the intracellular distribution of labeled biomolecules with sub-resolution accuracy. Unexpectedly, we find that RNA-binding proteins are partially excluded from the cytoplasmic volume adjacent to the plasma membrane that corresponds to the actin cortex. Complementary diffusion measurements of RNA-protein complexes suggest that a rudimentary model based on excluded volume interactions can explain this partitioning effect. Our results suggest the actin cortex meshwork may play a role in regulating the biomolecular content of the volume immediately adjacent to the plasma membrane.