Orientation of cell divisions is a key mechanism of tissue morphogenesis. In the growing Drosophila wing imaginal disc epithelium, most of the cell divisions in the central wing pouch are oriented along the proximal-distal (P-D) axis by the Dachsous-Fat-Dachs planar polarity pathway. However, cells at the periphery of the wing pouch instead tend to orient their divisions perpendicular to the P-D axis despite strong Dachs polarization. Here, we show that these circumferential divisions are oriented by circumferential mechanical forces that influence cell shapes and thus orient the mitotic spindle. We propose that this circumferential pattern of force is not generated locally by polarized constriction of individual epithelial cells. Instead, these forces emerge as a global tension pattern that appears to originate from differential rates of cell proliferation within the wing pouch. Accordingly, we show that localized overgrowth is sufficient to induce neighbouring cell stretching and reorientation of cell division. Our results suggest that patterned rates of cell proliferation can influence tissue mechanics and thus determine the orientation of cell divisions and tissue shape.
Tissues can grow in a particular direction by controlling the orientation of cell divisions. This phenomenon is evident in the developing Drosophila wing epithelium, where the tissue becomes elongated along the proximal-distal axis. We show that orientation of cell divisions in the wing requires planar polarization of an atypical myosin, Dachs. Our evidence suggests that Dachs constricts cell-cell junctions to alter the geometry of cell shapes at the apical surface, and that cell shape then determines the orientation of the mitotic spindle. Using a computational model of a growing epithelium, we show that polarized cell tension is sufficient to orient cell shapes, cell divisions, and tissue growth. Planar polarization of Dachs is ultimately oriented by long-range gradients emanating from compartment boundaries, and is therefore a mechanism linking these gradients with the control of tissue shape.
The molecular requirements and morphology of migrating cells can vary depending on matrix geometry; therefore, predicting the optimal migration strategy or the effect of experimental perturbation is difficult. We present a model of cell motility that encompasses actin-polymerization-based protrusions, actomyosin contractility, variable actin-plasma membrane linkage leading to membrane blebbing, cell-extracellular-matrix adhesion and varying extracellular matrix geometries. This is used to explore the theoretical requirements for rapid migration in different matrix geometries. Confined matrix geometries cause profound shifts in the relationship of adhesion and contractility to cell velocity; indeed, cell-matrix adhesion is dispensable for migration in discontinuous confined environments. The model is challenged to predict the effect of different combinations of kinase inhibitors and integrin depletion in vivo, and in confined matrices based on in vitro two-dimensional measurements. Intravital imaging is used to verify bleb-driven migration at tumour margins, and the predicted response to single and combinatorial manipulations.
TGF--induced Smad signal transduction from the membrane into the nucleus is not linear and unidirectional, but rather a dynamic network that couples Smad phosphorylation and dephosphorylation through continuous nucleocytoplasmic shuttling of Smads. To understand the quantitative behavior of this network, we have developed a tightly constrained computational model, exploiting the interplay between mathematical modeling and experimental strategies. The model simultaneously reproduces four distinct datasets with excellent accuracy and provides mechanistic insights into how the network operates. We use the model to make predictions about the outcome of fluorescence recovery after photobleaching experiments and the behavior of a functionally impaired Smad2 mutant, which we then verify experimentally. Successful model performance strongly supports the hypothesis of a dynamic maintenance of Smad nuclear accumulation during active signaling. The presented work establishes Smad nucleocytoplasmic shuttling as a dynamic network that flexibly transmits quantitative features of the extracellular TGF- signal, such as its duration and intensity, into the nucleus.systems biology ͉ TGF- ͉ computational modeling ͉ signaling network
Experimental and computer simulation studies have revealed the presence of a glass-like transition in the internal dynamics of hydrated proteins at approximately 200 K involving an increase of the amplitude of anharmonic dynamics. This increase in flexibility has been correlated with the onset of protein activity. Here, we determine the driving force behind the protein transition by performing molecular dynamics simulations of myoglobin surrounded by a shell of water. A dual heat bath method is used with which, in any given simulation, the protein and solvent are held at different temperatures, and sets of simulations are performed varying the temperature of the components. The results show that the protein transition is driven by a dynamical transition in the hydration water that induces increased fluctuations primarily in side chains in the external regions of the protein. The water transition involves activation of translational diffusion and occurs even in simulations where the protein atoms are held fixed.
Proteins exhibit a solvent-driven dynamical transition at 180-220 K, manifested by nonlinearity in the temperature dependence of the average mean-square displacement. Here, molecular dynamics simulations of hydrated myoglobin show that the onset of the transition at approximately 180 K is characterized by the appearance of a single double-well principal component mode involving a global motion of two groups of helices. As the temperature is raised a few more quasiharmonic and multiminimum components successively appear. The results indicate an underlying simplicity in the protein dynamical transition.
Epithelial tissues are composed of polarized cells with distinct apical and basolateral membrane domains. In the Drosophila ovarian follicle cell epithelium, apical membranes are specified by Crumbs (Crb), Stardust (Sdt), and the aPKC-Par6-cdc42 complex. Basolateral membranes are specified by Lethal giant larvae (Lgl), Discs large (Dlg), and Scribble (Scrib). Apical and basolateral determinants are known to act in a mutually antagonistic fashion, but it remains unclear how this interaction generates polarity. We have built a computer model of apicobasal polarity that suggests that the combination of positive feedback among apical determinants plus mutual antagonism between apical and basal determinants is essential for polarization. In agreement with this model, in vivo experiments define a positive feedback loop in which Crb self-recruits via Crb-Crb extracellular domain interactions, recruitment of Sdt-aPKC-Par6-cdc42, aPKC phosphorylation of Crb, and recruitment of Expanded (Ex) and Kibra (Kib) to prevent endocytic removal of Crb from the plasma membrane. Lgl antagonizes the operation of this feedback loop, explaining why apical determinants do not normally spread into the basolateral domain. Once Crb is removed from the plasma membrane, it undergoes recycling via Rab11 endosomes. Our results provide a dynamic model for understanding how epithelial polarity is maintained in Drosophila follicle cells.
SummaryEpithelia grow and undergo extensive rearrangements to achieve their final size and shape. Imaging the dynamics of tissue growth and morphogenesis is now possible with advances in time-lapse microscopy, but a true understanding of their complexities is limited by automated image analysis tools to extract quantitative data. To overcome such limitations, we have designed a new open-source image analysis toolkit called EpiTools. It provides user-friendly graphical user interfaces for accurately segmenting and tracking the contours of cell membrane signals obtained from 4D confocal imaging. It is designed for a broad audience, especially biologists with no computer-science background. Quantitative data extraction is integrated into a larger bioimaging platform, Icy, to increase the visibility and usability of our tools. We demonstrate the usefulness of EpiTools by analyzing Drosophila wing imaginal disc growth, revealing previously overlooked properties of this dynamic tissue, such as the patterns of cellular rearrangements.
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