During embryonic development, the proper formation of tissues and organs depends on cell shape changes that are governed by mechanical forces and tensions, but the biomolecular origin of those forces remains poorly understood. We will develop a new dynamic version of the vertex model for tissues to predict the interplay of signaling and forces that control organogenesis, in combination with in vivo microscopy and molecular biology techniques to quantitatively test those predictions. Kupffer's vesicle (KV) - which directs left-right patterning in the zebrafish embryo - is used as a model system. Preliminary work indicates that differential interfacial tensions inside KV cells drive programmed shape changes that establish a functional KV organ, and that biochemical signals and forces generated by cells external to KV also contribute to changing cell shapes inside KV. Therefore, this proposal will test the hypothesis that cell shape changes critical for KV organogenesis are a direct result of specific mechanical forces inside KV cells themselves as well as collective forces and signals generated by the cells surrounding KV.
Three specific aims are proposed:
Aim1 will use a mathematical vertex model to make predictions about interfacial tensions between cells in the KV, and compare predictions to intensities of labeled cellular cytoskeletal components along those interfaces.
Aim 2 will develop a novel dynamic vertex model and a complementary continuum model to predict the forces exerted and motions exhibited by cells surrounding the KV, and verify predictions using Particle Image Velocimetry.
Aim 3 will modulate Hedgehog signaling in the embryo to study how the morphogen gradient affects KV cell shape changes, modeled by coupling a reaction-diffusion-advection equation for the morphogen to a dynamic vertex model. Direct results of this work will include: a description of the mechanical and biochemical pathways that lead to KV tissue remodeling and organ function, an understanding of how different perturbations disrupt these pathways, and a new set of mathematical models for tissue mechanics. The long-term goal of this project is to develop and apply mathematics-based methodologies in vivo to discover new mechanisms underlying embryonic development and disease.
Defects that alter how an organ forms during embryonic development often result in congenital disease. Results from this study will advance our understanding of how genes interact with physical forces to control organ formation. This knowledge will be critical for developing approaches that predict, prevent or treat organ malformations and congenital diseases.
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