Scott Holley Ph.D.
Associate Professor of Molecular, Cellular, and Developmental Biology
Systems Developmental Biology, Gene Networks, Embryo Biomechanics
We use zebrafish as a model system to understand human development and the etiology of human disease. We study somitogenesis which is the process of creating the precursors to the vertebral column and musculature during embryogenesis. Aberrations in this process lead to a birth defect called spondylocostal dysostosis in humans. In addition, we study the mechanism of body elongation. Our research utilizes genetics, molecular biology, advanced imaging, quantitative image analysis and computational modeling. Ultimately, we want to understand how the combined interactions between genes, cells and cellular mechanics facilitate the emergence of higher levels of organization in embryonic development and tissue homeostasis.
Extensive Research Description
The physical characteristics of the cellular environment influence cell differentiation, and reciprocally, cell differentiation often manifests as alterations in adhesion, rigidity and motility. Some of the most rapid and interdependent changes in both physical form and cell differentiation occur during embryonic development. However, we still have a poorly integrated understanding of the relationships between genetic control and the physical characteristics of tissues.
The tailbud is the posterior leading edge of the growing vertebrate embryo consisting of motile progenitors of the axial skeleton, musculature and spinal cord. In a recent study, we measured the 3-D cell flow field of the zebrafish tailbud and identified changes in tissue fluidity revealed by reductions in the coherence of cell motion without alteration of cell velocities. We found a directed posterior flow wherein the polarization between individual cell motion is high reflecting ordered collective migration. At the posterior tip of the tailbud, this flow makes sharp bilateral turns facilitated by with extensive cell mixing due to increased directional variability of individual cell motions. Genetic perturbation of cell signaling or cell adhesion reduces the coherence of the flow but has different consequence for trunk and tail extension. Interplay between the coherence and rate of cell flow determines whether congestion forms within the flow and the body axis becomes contorted. Future studies will build upon this systems understanding of tissue fluidity within the tailbud by incorporating additional signaling pathways and cell-extracellular matrix interactions, cell-cell adhesion as well as developing more accurate computer models of the cell flow. We are also studying the physical forces within tailbud and the reciprocal relationships between genetic control the physical properties of the cellular and tissue environment. These studies will increase understanding of how a tissue’s physical characteristics impacts morphogenesis, tissue homeostasis and disease in humans.