Investigating how mechanical connectivity yields developmental robustness

摘要 对于生物体的命运来说，关键的形态发生过程甚至是可重复地发生是至关重要的。 在组织损伤或环境干扰下。虽然已经知道了很多关于遗传冗余和 监管实现了强劲的发展，人们对组织如何机械地确保 受扰时可重现的形状变化。这个项目揭示了人类是如何通过身体互动 细胞机械地对具有挑战性的条件做出反应，并修改它们的集体行为，以仍然塑造 正确的最终形状。 细胞协调组织规模的力和运动的一种方式是通过直接的机械 关系。事实上，许多发育中的组织表现出肌动球蛋白连接的超细胞网络 连接数百个细胞。一个巨大的障碍是对亚细胞进行成像和量化的挑战 组织尺度上的蛋白质。我采用了一种最初用于跟踪高噪声的拓扑平滑算法 宇宙中星系的丝状结构到追踪高噪声肌球蛋白结构的数据 共焦图像。这使得第一次量化了整个细胞上的肌球蛋白网络 组织随着发育时间的推移。随后的分析采用了网络理论中的技术，使我能够 确认果蝇果蝇胚胎在腹侧沟形成过程中的强健折叠是机械的 由横跨其腹侧细胞的超细胞网络中的模式确保。 这一新发现的超细胞网络在协调稳健的形状变化方面的重要性 强调需要全面了解超蜂窝网络是如何形成的，以及它们的 模式影响一组细胞的功能和稳健性。在组织层面上破译健壮性， 在必须考虑数百个细胞的位移和命运的情况下，需要界面上的技术 细胞与发育生物学、生物物理学和计算机科学。拟议的项目将耗费大量资金。 跨学科方法，以确定超细胞网络模式是如何在细胞内受到分子控制的 水平，并通过组织约束。此外，组织水平模式的异质性如何影响形态发生 将解决健壮性问题。结合这一对超细胞结构和功能的全面研究 网络将代表一种新的方式来解释不同发育中的组织的机械稳健性。AS 机械稳健性的广义描述有可能发现新的路径来预测和 控制组织畸形，这将是发育生物学和 胎儿医学。

ABSTRACT It is essential for the fate of an organism that key morphogenetic processes occur reproducibly even under tissue damage or environmental perturbations. While much is known about how genetic redundancy and regulation achieves robust development, less is understood about how a tissue mechanically ensures reproducible shape change when perturbed. This project uncovers how populations of physically interacting cells mechanically respond to challenging conditions and modify their collective behavior to still sculpt the correct final shape. One way for cells to coordinate tissue-scale forces and movements is through direct mechanical connections. In fact, many developing tissues exhibit supracellular networks of actomyosin connections that link hundreds of cells. A large roadblock has been with the challenges of imaging and quantifying subcellular protein at the tissue scale. I adapted a topological smoothing algorithm originally used to trace high-noise filamentous structure of galaxies in the Universe to data to trace high-noise filamentous myosin structure in confocal images. This allowed for the first quantification of a supracellular myosin network across an entire tissue over developmental time. Subsequent analysis adopting techniques from network theory allowed me to identify that the robust folding of the Drosophila fruit fly embryo during ventral furrow formation is mechanically ensured by patterns in the supracellular network spanning its ventral cells. This newly discovered importance of supracellular networks in coordinating robust shape change highlights the need for a comprehensive understanding of how supracellular networks form, and how their patterns impact the function and robustness of a population of cells. Deciphering robustness at the tissue-level, where the displacement and fate of hundreds of cells must be considered, requires techniques at the interface of cell and developmental biology, biophysics and computer science. The proposed project will take a highly interdisciplinary approach to identify how supracellular network patterns are controlled molecularly, at the cell level, and via tissue constraints. As well, how heterogeneity in tissue-level patterns impacts morphogenetic robustness will be addressed. Together this comprehensive study of the structure and function of supracellular networks will represent a new way to interpret mechanical robustness across diverse developing tissues. As well, a generalized description of mechanical robustness has the potential to uncover new paths to predict and control tissue malformation, which would represent a significant advance for both developmental biology and fetal medicine.