Multi-scale feedbacks for robust organ development

项目摘要 成功的胚胎发育的标志之一是可再生性和健壮性。 形成具有正确形状和大小的器官。器官形态发生的失败会导致 发育障碍，终身出生缺陷，在某些情况下，胚胎致死， 流产为了解决复杂的形式是如何从简单的组织中复制出来的， 跨物种的研究提供了一个简单的机制框架， 模式细胞力学来驱动组织形态发生。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 (iii)组织几何形状的指导作用。为了解决这些悬而未决的挑战， 在形态发生中，我们将利用所有脊椎动物生物体共有的典型器官-- 内耳的半规管，在一个可访问的遗传模型系统-斑马鱼。的 三个管道是相互正交的，这种精确的角度结构是必要的， 检测头部旋转并保持平衡。运河的复杂形态 从一个简单的胚胎组织的拓扑重塑，使其成为最 几何学上的复杂和精确的形态发生过程适合研究。探讨 如何运河形态建成实现鲁棒性，我们将建立一个新的实验范式 通过利用高分辨率显微镜，单细胞转录组数据，统计分析， 遗传、物理和生物物理扰动，以及预测性物理建模。这种范式 将用于：（i）测量组织模式和形态的变化;（ii）添加变化 用于解剖出基因编码的 指令与其他监管机制，以及（iii）系统地调查物理 来自组织几何形状的约束和通过“管道化”中的机械转换的反馈 发展过程中的变化。这些创新、独特但互补的方法将 提供一个新的综合框架，将信息的相互流动封装在 遗传模式、细胞行为和组织几何形状，以实现成功的胚胎发育。这 该框架将用于识别体内发育缺陷和障碍的病因。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， 也会影响人类的健康。

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.