Modeling the Structural and Mechanical Properties of Tissue During Zebrafish Tailbud Elongation

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Cells need to move collectively in nearly all biological processes at the tissue scale. One of the most significant challenges to understanding collective cell motion is determining how single-cell motility strategies affect collective cell behavior at the tissue level. For example, do cells actively sense the direction of motion of their neighbors, or do cells primarily rely on cell-cell adhesion and repulsion from their neighbors to move collectively? To understand the mapping from single-cell properties to collective migration, the PI proposes a combined experimental and computational approach to investigate collective cell migration during convergent extension processes in the developing zebrafish spinal column. Using confocal microscopy and genetic variants, the PI will measure how alterations to cell-cell adhesion and planar cell polarity alter the flow of cells in three dimensions. He will then simulate convergent extension processes in the developing zebrafish spinal column using the deformable particle (DP) model in two and three spatial dimensions in realistic boundary conditions that are both deformable and contractile. The DP model also makes it possible to systematically vary the cell shape, cell-cell adhesion, and single-cell motility strategy. The PI will compare the results of the simulations to those obtained from 3D imaging of cell motion and shape of both wildtype and mutant zebrafish embryos. The proposed work will provide two significant advances to our understanding of collective cell motion: (1) how can we map single-cell properties to features of collective cell migration, and (2) what is a sufficient degree of model complexity to capture important features of collective cell migration? Currently, models for collective cell migration do not model true cell deformability and realistic cell motility strategies, but they can qualitatively capture several aspects of collective cell migration. These proposed simulations of deformable particles in both two and three dimensions, along with three-dimensional imaging of live tissue, will allow the team to determine what model ingredients are required to quantitatively describe collective cell migration. This project also includes a number of education and outreach activities that leverage the PIs' involvement in the Integrated Graduate Program in Physical and Engineering Biology. Initiatives will include mentoring high school and undergraduate students in research, developing a course module on computational modeling of cell migration during zebrafish spinal column development, and hosting short courses aimed at improving the presentation of scientific topics to non-scientific audiences by graduate students.The PI proposes coordinated experimental and computational studies to understand the role of cell shape change, motility strategy, and adhesion on collective cell motion during the convergent extension process in the elongating tail bud of zebrafish embryos. The PI will develop novel deformable particle (DP) model simulations in dynamic, deformable boundaries in both two and three spatial dimensions, which can quantitatively describe cell- and tissue-level deformation of developing zebrafish embryos and predict the effect of changes to single-cell biophysical parameters on collective cell motion. Complementary experiments will be performed on zebrafish embryos with varied cell motility and cell-cell adhesion through mutations to the planar cell polarity pathway and cadherin-mediated adhesion that enable the predictions of the DP model to be tested experimentally.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.