Multi-scale feedbacks for robust organ development

项目总结 胚胎发育成功的标志之一是可重复性和健壮 形成具有合适形状和大小的器官。器官形态发生障碍可导致 发育障碍，终身出生缺陷，在某些情况下，胚胎死亡和 流产。为了解决复杂形式如何从简单组织中重复产生的问题，研究 跨物种的研究提供了一个简单的机械框架，其中遗传信息 形成驱动组织形态发生的细胞力学模式。然而，这个简单的框架， 在信息从基因到细胞再到组织的层次流动中，未能解释：(I) 生物噪声引起组织模式的变化，(Ii)多尺度反馈相互作用，以及 (3)组织几何学的指导作用。要解决器官领域的这些突出挑战 形态发生，我们将利用所有脊椎动物共有的一个示范器官-- 在一个可访问的遗传模型系统-斑马鱼中，内耳的半规管。这个 三条运河相互垂直，这种精确的角度结构需要 检测头部旋转并保持平衡。复杂的运河形态出现了 从一个简单的胚胎组织的拓扑重塑，使其成为最 几何上复杂和精确的形态发生过程是可以研究的。去调查 如何实现根管形态发生的稳健性，我们将建立一个新的实验范式 通过利用高分辨率显微镜，单细胞转录数据，统计分析， 遗传、物理和生物物理扰动，以及预测性物理模型。这一范式 将被部署到：(1)测量组织模式和形态的变化；(2)增加变化 到组织模式，以剖析出基因编码的 指令与其他调节机制的对比，以及(Iii)系统地调查物理 “管化”过程中组织几何和机械转导反馈的制约 发育过程中的变异。这些创新、独特但互补的方法将 提供一个新的集成框架，该框架封装了 成功胚胎发育的遗传模式、细胞行为和组织几何形状。这 框架将被用来确定体内发育缺陷和疾病的病因。通过 通过揭示出生缺陷或流产的潜在原因，我们的研究可能，从长远来看， 也影响了人类的医疗保健。

PROJECT SUMMARY One of the hallmarks of successful embryonic development is the reproducible and robust formation of organs with the right shape and size. Failures in organ morphogenesis can result in developmental disorders, lifelong birth defects, and, in some cases, embryonic lethality and miscarriage. To address how complex forms reproducibly arise from simple tissues, research studies across species have provided a simple mechanistic framework, where genetic-information patterns cellular mechanics to drive tissue morphogenesis. However, this simple framework, where information flows hierarchically from genes to cells to tissues, fails to account for: (i) biological noise causing variations in tissue patterns, (ii) multi-scale feedback interactions, and (iii) guiding roles of tissue geometry. To address these outstanding challenges in organ morphogenesis, we will utilize an exemplary organ common to all vertebrate organisms— the semicircular canals of the inner ear, in an accessible genetic model system— the zebrafish. The three canals are mutually orthogonal, and this precise angular architecture is required for detecting head rotations and maintaining balance. The intricate morphology of the canals arises from the topological remodeling of a simple embryonic tissue, making it one of the most geometrically complex and accurate morphogenic processes amenable to study. To investigate how canal morphogenesis achieves robustness, we will establish a new experimental paradigm by leveraging high-resolution microscopy, single-cell transcriptomic data, statistical analysis, genetic, physical, and biophysical perturbations, and predictive physical modelling. This paradigm will be deployed to: (i) measure variations in tissue patterns and morphologies; (ii) add variations to tissue patterns for dissecting out the respective contributions of genetically-encoded instructions versus other regulatory mechanisms, and (iii) systematically investigate the physical constraints from tissue geometry and feedbacks through mechano-transduction in “canalizing” variations during development. These innovative, distinct yet complementary approaches will deliver a new, integrative framework encapsulating reciprocal flow of information between genetic-patterns, cell behaviors and tissue geometry for successful embryonic development. This framework will be used to identify the etiology of developmental defects and disorders in vivo. By revealing underlying causes for birth defects or miscarriages, our research may, in the long term, also impact human healthcare.