The Physical Basis of Morphogenesis: Shaping and Patterning of Tissues via Cell-Cell Forces

Somehow, a fertilized egg develops into a multicellular organism with several organs that perform distinct functions. Much research regarding the development of multi-cellular organisms is chemical in nature: from networks of interacting intracellular bio-molecules to intercellular gradients of secreted chemicals. The role of mechanical forces, between neighboring cells or between cells and their environment, in development is often neglected. Here, based on models of mechanical forces during development, we study three processes: cone mosaic formation in zebrafish, apical stress fiber generation in Drosophila, and neural induction in stem cell colonies. One of the most ordered vertebrate tissues, the zebrafish cone mosaic is a crystalline array of cells on the retina’s hemispheric surface. The cone mosaic grows from the retina’s rim; because of geometric constraints, defects form to maintain approximately constant cell spacing. These defects line up from the center to the periphery of the retina as it grows. A model based on chemical signaling in a fixed cell packing generates many excess defects; in contrast, a model based on repulsive interactions between cone cells reproduces the spatial distribution of defects observed in the retina. Unlike influential studies of the Drosophila R8 photoreceptor array, our findings suggest that cell motion governed by repulsive cell-cell interactions can play a key role in generating regular patterns in living systems. Rather than repulsive intercellular interactions, in Drosophila we study how an entire tissue responds to morphogenetic forces from groups of neighboring cells. Apical stress fibers (aSFs) form to resist cell elongation. Importantly, the number of aSFs per cell scales with cell area to prevent elongation of large cells. To understand this scaling between mechanical response and cell area, we develop a model to predict the number of aSFs within any given cell based on its shape. Since aSFs nucleate and break at tricellular junctions (TCJs), the number of aSFs in each cell depends on the cell’s number of TCJs and the spacing between those TCJs. Our findings highlight how, based on area, cells scale their mechanical responses to resist deformations. Finally, we study how mechanical stresses can bias cell fate. Our experimental system is a stem-cell-based model of neural induction, the process by which certain cells in the outer embryonic layer become neural. Two domains, the neural plate and the neural plate border (NPB), form. Motivated by experimental observations, we construct a mathematical model that couples cell fate and cell mechanical stress. In our model, cells at the colony boundary generate a fate pattern by transmitting forces to interior cells. Our mathematical model predicts that the NPB’s width depends non-monotonically on the stiffness of the cells’ substrate. With experimental validation of this prediction, we argue that cells can communicate with each other via mechanical forces, biasing each other’s fates. Mechanical forces guide the shaping and patterning of tissues, from juvenile zebrafish to Drosophila embryos to human stem cells. Repulsion between cells of fixed fate can generate a crystalline array of cells. By helping cells resist deformations due to external stresses, apical stress fibers can tune a tissue’s final shape. Mechanical stresses, transmitted between cells, can produce fate patterns with a length scale that depends on the extracellular matrix’s stiffness. Starting as early as gastrulation, when three embryonic layers form, mechanical forces between cells shape the embryo and its constituent tissues into proper form.PhDBiophysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/162846/1/nunley_1.pd