The orderly packing and precise arrangement of individual epithelial cells is essential to the functioning of many biological tissues, including sensory structures in animals such as photoreceptors in the retina of the eye and hair cells in the auditory epithelium of the inner ear. Various biological and physical influences can affect epithelial cell geometry, among them cell-cell adhesion, cytoskeletal dynamics, and macroscopic mechanical stress, but the changes in cell shape and position that generate planar geometric ordering are still only partially understood. Ultimately, quantitative physical models will be needed to unravel the dynamic regulatory behavior responsible for the regular arrays of cells seen in many biological systems. The proposed research will be accomplished by an interdisciplinary team that relies on ideas and techniques from both statistical physics and developmental biology. The goal is to generate mathematical models that can be tested directly with biological experiments, and with these models to discover mechanisms that position cone photoreceptors in a precise array in the zebrafish retina. The computational models developed in this project will be the first to explore how differences in cell-cell affinities combined with directed mechanical stresses can generate longer-ranged order in an epithelium. These studies will also provide a unique understanding of the biological and physical mechanisms underlying the planar organization of vertebrate photoreceptors in the developing eye. A research team diverse in gender, ethnicity, and scientific discipline will be built through continuing involvement of the PI, Co-PI and postdoctoral researcher in campus-based and external programs to promote diversity of undergraduate and graduate science students. A course module on biological modeling will be developed for graduate students, and new computational tools for understanding the emergence of biological form will be made freely available.
Animals begin their life by undergoing a remarkable process of self-organization: Starting from a tiny, single-celled egg, they develop into an incredibly complex organism. Moreover, they do so without centralized control—no master builder directs each cell to its correct position in the final body plan. How exactly living cells are instead able to collaborate to create, seemingly out of nothing, precisely constructed tissues and organs is the central question of developmental biology. This project studied an especially compelling example of such self-organization of cell position and identity, found in cone photoreceptors in the zebrafish eye. To discover the biological mechanisms of self-organization, we used a combination of microscopic observations of the planar pattern of cone photoreceptors, perturbation of this pattern following experimental disruptions, and computer simulations. These techniques allowed us both to understand the cone patterns in fish eyes more deeply and to tease out broader principles that might apply in other animals (including humans). The fundamental knowledge about biological self-organization that we have gained has potential applications ranging from new treatments for retinal disorders to the design of synthetic self-organizing systems inspired by the mechanisms at work in the eye. More specifically, this project combined biological experiments with mathematical modeling to study the emergence of the strikingly crystalline arrangement of cone photoreceptor cells in the zebrafish retina. The guiding hypothesis for the formation of this ordered lattice included several elements: coupling between a progressive, linear wave of cell production; planar cell polarity and polarized cell-cell adhesion; and anisotropic mechanical stresses imposed on the retinal epithelium by the annular ligament, a rigid ring of tissue that surrounds the retinal margin. Results summarized in two publications showed that a mathematical model of the interaction between, orderly production of new photoreceptor cells, mechanical forces, cell shape, and planar polarized cell-cell adhesion could reproduce many observed features of the regular arrangement of cones; the model correctly predicted the presence of strongly anisotropic interactions between cells in perturbed retina. A series of experimental manipulations to disrupt the pattern of cell proliferation, or the differentiation of cones, or the global mechanical stress on the retinal epithelium, altered the cone mosaic pattern in predictable ways. As a collaboration between a physicist and a biologist, this project created opportunities for interdisciplinary education at many levels, from high school students to post-graduate training. The investigators placed a special emphasis on involving students from traditionally underrepresented backgrounds in research early in their undergraduate careers.
