Dynamical maintenance of left-right symmetry during vertebrate development

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Broad Objective: Maintaining anatomical symmetry in vertebrates is essential for proper physiological function, and loss of symmetry in ribs and vertebrae can lead to serious conditions such as scoliosis and impairments of appropriate breathing and posture. This project will explore the developmental emergence of left-right symmetry, combining biological experiments on wild-type mice and a model of early loss of symmetry with mathematical models of gene expression and molecule distributions. Through these studies, the project will provide new important insight into the determinants of body (a)symmetry. Specific Aims and Research Design: The somites are the embryonic structures giving rise to the vertebrae and rib cage. They are formed at early phases of embryonic development and emerge progressively in pairs of paraxial mesoderm blocks on both sides of the midline in a highly symmetric manner. The symmetry of the somites is actively maintained through mechanisms controlled by retinoic acid (RA) signaling. Indeed, animals deficient in RA exhibit an asymmetric somite formation. This proposal will investigate this RA-mediated symmetry maintenance mechanisms by combining experiments on RA-deficient mice with mathematical models of somitogenesis. In Aim 1, to investigate the dynamical mechanism of somite formation in wild-type and RA-deficient embryos, we will characterize finely the somite formation timing, period, and positions in mouse embryos through live imaging techniques coupled with and topological data analysis. In Aim 2, to study the genetic mechanism involved in the segmentation clock, which controls the spatio-temporal formation of somites, the same live-imaging setup will be leveraged to extract the dynamics of the segmentation clock in mouse embryos. This data will be used to develop and specify a theoretical model of somitogenesis which will in turn allow exploring the determinants of symmetry maintenance and its breakdown. To explore how asymmetry may arise and be buffered by RA, Aim 3 proposes to study the origin of asymmetry in RA-deficient mouse. It will rely on the development of computational fluid dynamics simulations to analyze the global distribution of key signaling molecules as they are transported in fluids driven by cilia movements. This will be coupled to reaction-diffusion systems and their dynamics will be explored to investigate how RA-mediated mechanism can buffer any initial asymmetry in molecular concentrations.