We investigate the behavior of systems of cells with intracellular molecular oscillators ("clocks") where cell-cell adhesion is mediated by differences in clock phase between neighbors. This is ...motivated by phenomena in developmental biology and in aggregative multicellularity of unicellular organisms. In such systems, aggregation co-occurs with clock synchronization. To account for the effects of spatially extended cells, we use the Cellular Potts Model (CPM), a lattice agent-based model. We find four distinct possible phases: global synchronization, local synchronization, incoherence, and anti-synchronization (checkerboard patterns). We characterize these phases via order parameters. In the case of global synchrony, the speed of synchronization depends on the adhesive effects of the clocks. Synchronization happens fastest when cells in opposite phases adhere the strongest ("opposites attract"). When cells of the same clock phase adhere the strongest ("like attracts like"), synchronization is slower. Surprisingly, the slowest synchronization happens in the diffusive mixing case, where cell-cell adhesion is independent of clock phase. We briefly discuss potential applications of the model, such as pattern formation in the auditory sensory epithelium.
Genotypic variation, environmental variation, and their interaction may produce variation in the developmental process and cause phenotypic differences among individuals. Developmental noise, which ...arises during development from stochasticity in cellular and molecular processes when genotype and environment are fixed, also contributes to phenotypic variation. While evolutionary biology has long focused on teasing apart the relative contribution of genes and environment to phenotypic variation, our understanding of the role of developmental noise has lagged due to technical difficulties in directly measuring the contribution of developmental noise. The influence of developmental noise is likely underestimated in studies of phenotypic variation due to intrinsic mechanisms within organisms that stabilize phenotypes and decrease variation. Since we are just beginning to appreciate the extent to which phenotypic variation due to stochasticity is potentially adaptive, the contribution of developmental noise to phenotypic variation must be separated and measured to fully understand its role in evolution. Here, we show that variation in the component of the developmental process corresponding to environmental and genetic factors (here treated together as a unit called the LALI-type) versus the contribution of developmental noise, can be distinguished for leopard gecko (Eublepharis macularius) head color patterns using mathematical simulations that model the role of random variation (corresponding to developmental noise) in patterning. Specifically, we modified the parameters of simulations corresponding to variation in the LALI-type to generate the full range of phenotypic variation in color pattern seen on the heads of eight leopard geckos. We observed that over the range of these parameters, variation in color pattern due to LALI-type variation exceeds that due to developmental noise in the studied gecko cohort. However, the effect of developmental noise on patterning is also substantial. Our approach addresses one of the major goals of evolutionary biology: to quantify the role of stochasticity in shaping phenotypic variation.
Animal color patterns are widely studied in ecology, evolution, and through mathematical modeling. Patterns may vary among distinct body parts such as the head, trunk or tail. As large amounts of ...photographic data is becoming more easily available, there is a growing need for general quantitative methods for capturing and analyzing the full complexity and details of pattern variation. Detailed information on variation in color pattern elements is necessary to understand how patterns are produced and established during development, and which evolutionary forces may constrain such a variation. Here, we develop an approach to capture and analyze variation in melanistic color pattern elements in leopard geckos. We use this data to study the variation among different body parts of leopard geckos and to draw inferences about their development. We compare patterns using 14 different indices such as the ratio of melanistic versus total area, the ellipticity of spots, and the size of spots and use these to define a composite distance between two patterns. Pattern presence/absence among the different body parts indicates a clear pathway of pattern establishment from the head to the back legs. Together with weak within-individual correlation between leg patterns and main body patterns, this suggests that pattern establishment in the head and tail may be independent from the rest of the body. We found that patterns vary greatest in size and density of the spots among body parts and individuals, but little in their average shapes. We also found a correlation between the melanistic patterns of the two front legs, as well as the two back legs, and also between the head, tail and trunk, especially for the density and size of the spots, but not their shape or inter-spot distance. Our data collection and analysis approach can be applied to other organisms to study variation in color patterns between body parts and to address questions on pattern formation and establishment in animals.
We propose a numerical approach that combines a radial basis function (RBF) meshless approximation with a finite difference discretization to solve a nonlinear system of integro-differential ...equations. The equations are of advection-reaction-diffusion type modeling the formation of pre-cartilage condensations in embryonic chicken limbs. The computational domain is four dimensional in the sense that the cell density depends continuously on two spatial variables as well as two structure variables, namely membrane-bound counterreceptor densities. The biologically proper Dirichlet boundary conditions imposed in the semi-infinite structure variable region is in favor of a meshless method with Gaussian basis functions. Coupled with WENO5 finite difference spatial discretization and the method of integrating factors, the time integration via method of lines achieves optimal complexity. In addition, the proposed scheme can be extended to similar models with more general boundary conditions. Numerical results are provided to showcase the validity of the scheme.
We describe a 'reactor-diffusion' mechanism for precartilage condensation based on recent experiments on chondrogenesis in the early vertebrate limb and additional hypotheses. Cellular ...differentiation of mesenchymal cells into subtypes with different fibroblast growth factor (FGF) receptors occurs in the presence of spatio-temporal variations of FGFs and transforming growth factor-betas (TGF-βs). One class of differentiated cells produces elevated quantities of the extracellular matrix protein fibronectin, which initiates adhesion-mediated preskeletal mesenchymal condensation. The same class of cells also produces an FGF-dependent laterally acting inhibitor that keeps condensations from expanding beyond a critical size. We show that this 'reactor-diffusion' mechanism leads naturally to patterning consistent with skeletal form, and describe simulations of spatio-temporal distribution of these differentiated cell types and the TGF-β and inhibitor concentrations in the developing limb bud.
We consider the geometric optics problem of finding a system of two reflectors that transform a spherical wavefront into a beam of parallel rays with prescribed intensity distribution. Using ...techniques from optimal transportation theory, it has been shown previously that this problem is equivalent to an infinite-dimensional linear programming (LP) problem. Here we investigate techniques for constructing the two reflectors numerically by considering the finite-dimensional LP problems which arise as approximations to the infinite-dimensional problem. A straightforward discretization has the disadvantage that the number of constraints increases rapidly with the mesh size, so only very coarse meshes are practical. To address this well-known issue we propose an iterative solution scheme. In each step, an LP problem is solved, where information from the previous iteration step is used to reduce the number of necessary constraints. As an illustration, we apply our proposed scheme to solve a problem with synthetic data, demonstrating that the method allows for much finer meshes than a simple discretization. We also give evidence that the scheme converges. There exists a growing literature for the application of optimal transportation theory to other beam shaping problems, and our proposed scheme is easy to adapt for these problems as well.
Ovarian cancer is amongst the most morbid of gynecological malignancies due to its diagnosis at an advanced stage, a transcoelomic mode of metastasis, and rapid transition to chemotherapeutic ...resistance. Like all other malignancies, the progression of ovarian cancer may be interpreted as an emergent outcome of the conflict between metastasizing cancer cells and the natural defense mounted by microenvironmental barriers to such migration. Here, we asked whether senescence in coelom-lining mesothelia, brought about by drug exposure, affects their interaction with disseminated ovarian cancer cells. We observed that cancer cells adhered faster on senescent human and murine mesothelial monolayers than on non-senescent controls. Time-lapse epifluorescence microscopy showed that mesothelial cells were cleared by a host of cancer cells that surrounded the former, even under sub-confluent conditions. A multiscale computational model predicted that such colocalized mesothelial clearance under sub-confluence requires greater adhesion between cancer cells and senescent mesothelia. Consistent with the prediction, we observed that senescent mesothelia expressed an extracellular matrix with higher levels of fibronectin, laminins and hyaluronan than non-senescent controls. On senescent matrix, cancer cells adhered more efficiently, spread better, and moved faster and persistently, aiding the spread of cancer. Inhibition assays using RGD cyclopeptides suggested the adhesion was predominantly contributed by fibronectin and laminin. These findings led us to propose that the senescence-associated matrisomal phenotype of peritoneal barriers enhances the colonization of invading ovarian cancer cells contributing to the metastatic burden associated with the disease.
The paired appendages (fins or limbs) of jawed vertebrates contain an endoskeleton consisting of nodules, bars and, in some groups, plates of cartilage, or bone arising from replacement of ...cartilaginous templates. The generation of the endoskeletal elements occurs by processes involving production and diffusion of morphogens, with, variously, positive and negative feedback circuits, adhesion, and receptor dynamics with similarities to the mechanism for chemical pattern formation proposed by Alan Turing. This review presents a unified interpretation of the evolution and functioning of these mechanisms. Studies are described indicating that protocondensations, compacted mesenchymal cell aggregates that prefigure the appendicular skeleton, arise through the adhesive activity of galectin-1, a matricellular protein with skeletogenic homologs in all jawed vertebrates. In the cartilaginous and lobe-finned fishes (and to a variable extent in ray-finned fishes) it additionally cooperates with an isoform of galectin-8 to constitute a self-organizing network capable of generating arrays of preskeletal nodules, bars and plates. Further, in the tetrapods, a putative galectin-8 control module was acquired that may have enabled proximodistal increase in the number of protocondensations. In parallel to this, other self-organizing networks emerged that acted, via Bmp, Wnt, Sox9 and Runx2, as well as transforming factor-β and fibronectin, to convert protocondensations into skeletal tissues. The progressive appearance and integration of these skeletogenic networks over evolution occurred in the context of an independently evolved system of Hox protein and Shh gradients that interfaced with them to tune the spatial wavelengths and refine the identities of the resulting arrays of elements.
The mesenchymal tissue of the developing vertebrate limb bud is an excitable medium that sustains both spatial and temporal periodic phenomena. The first of these is the outcome of general ...Turing-type reaction-diffusion dynamics that generate spatial standing waves of cell condensations. These condensations are transformed into the nodules and rods of the cartilaginous, and eventually (in most species) the bony, endoskeleton. In the second, temporal periodicity results from intracellular regulatory dynamics that generate oscillations in the expression of one or more gene whose products modulate the spatial patterning system. Here we review experimental evidence from the chicken embryo, interpreted by a set of mathematical and computational models, that the spatial wave-forming system is based on two glycan-binding proteins, galectin-1A and galectin-8 in interaction with each other and the cells that produce them, and that the temporal oscillation occurs in the expression of the transcriptional coregulator Hes1. The multicellular synchronization of the Hes1 oscillation across the limb bud serves to coordinate the biochemical states of the mesenchymal cells globally, thereby refining and sharpening the spatial pattern. Significantly, the wave-forming reaction-diffusion-based mechanism itself, unlike most Turing-type systems, does not contain an oscillatory core, and may have evolved to this condition as it came to incorporate the cell-matrix adhesion module that enabled its pattern-forming capability.
PDF
