Dynamical maintenance of left-right symmetry during vertebrate development

广泛的目标：保持脊椎动物的解剖对称性对于适当的生理功能是必不可少的 肋骨和脊椎的功能和对称性的丧失会导致严重的情况，如脊柱侧弯和 适当的呼吸和姿势的障碍。这个项目将探索发展中的涌现 结合野生型小鼠的生物学实验和小鼠早期脑功能丧失的模型。 对称性与基因表达和分子分布的数学模型。通过这些研究， 该项目将为人体(A)对称性的决定因素提供新的重要见解。 具体目标和研究设计：体节是胚胎结构，产生 椎骨和肋骨。它们在胚胎发育的早期阶段形成并出现 逐渐在中线两侧以高度对称的方式成对地形成近轴中胚层块 举止。体节的对称性是通过维甲酸控制的机制主动维持的。 酸(RA)信号。事实上，RA缺乏的动物表现出不对称的体节形成。这项建议 我将结合RA缺陷小鼠的实验和体细胞发生的数学模型来研究这种RA介导的对称性维持机制。 目的1，探讨野生型和RA缺陷型体节形成的动力学机制 胚胎，我们将详细描述小鼠胚胎中体节形成的时间、周期和位置。 通过现场成像技术与拓扑数据相结合进行分析。在目标2中，研究遗传 控制体节形成的分段时钟所涉及的机制， 将利用相同的实时成像设置来提取鼠标分段时钟的动态 胚胎。这些数据将被用来开发和指定体细胞发生的理论模型，该模型将在 反过来，我们可以探索对称性保持的决定因素及其破坏。探索如何 不对称性可能会出现，并被RA缓冲，目的3建议研究RA缺陷小鼠不对称性的起源。它将依靠计算流体力学模拟的发展来分析 关键信号分子在纤毛运动驱动的流体中运输时的全球分布。 这将与反应-扩散系统相耦合，并将探索它们的动力学，以研究如何 RA介导的机制可以缓冲分子浓度的任何初始不对称。

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.