Tissue Mechanics in Neural Tube Morphogenesis

神经管形态发生中的组织力学

• 批准号: EP/X023761/1
• 负责人: Fengzhu Xiong
• 金额: $ 159.82万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX023761%2F1
• 关键词: Tissue; Mechanics; Neural; Tube; Morphogenesis

Tissue morphogenesis depends on the intrinsic and extrinsic forces acting on tissue soft matter properties. These physical quantities are the final effectors and the converging point of the genetic and environmental interactions that control morphogenesis. In the developing neural tube, a multitude of genetic and cellular processes contribute to its folding and closure, yet how they regulate tissue mechanics remain unclear. The failure of closure leads to neural tube defects (NTDs), a class of common developmental abnormalities and a worldwide health burden. To resolve NTD etiology, it is essential to define the tissue forces that drive neural tube folding and uncover their genetic and cellular origins and regulation. The avian neural tube shares key morphogenetic characteristics with humans while providing easy access to imaging and mechanical tools. Recently, I and colleagues developed a novel force probe for direct tissue stress measurement and loading in live avian embryos. Importantly, we identified a compression force from the presomitic mesoderm and a change of global tissue tension, both required for neural tube folding suggesting previously unrecognized NTD causes. The dynamics of these forces, tissue rheological properties, and their interplay with cellular and genetic processes are unknown. Here, combining quantitative tissue mechanics and imaging, I propose to 1) systematically map tissue mechanics and cell and extracellular matrix organization of the avian neural tube and neighbouring tissues; 2) elucidate the role of planar cell polarity and folate pathways in inter-tissue mechanics during neural folding; 3) define the cellular mechanisms controlling the formation and pressure of the neural tube lumen. Our insights will transform our understanding of NTDs and more generally the mechanics of epithelial morphogenesis. Our quantitative platform will have broad applications in other models of morphogenesis, including human organoids.

组织形态发生取决于作用于组织软物质性质的内在和外在力量。这些物理量是控制形态发生的遗传和环境相互作用的最终效应器和汇合点。在发育中的神经管中，许多遗传和细胞过程有助于其折叠和闭合，但它们如何调节组织力学尚不清楚。神经管闭合失败导致神经管缺陷（NTDs），一类常见的发育异常和世界范围内的健康负担。为了解决NTD的病因，必须确定驱动神经管折叠的组织力，并揭示其遗传和细胞起源和调控。鸟类神经管与人类具有关键的形态发生特征，同时提供了方便的成像和机械工具。最近，我和同事们开发了一种新的力探针，用于直接测量活禽胚胎的组织应力和加载。重要的是，我们发现了来自发育前中胚层的压缩力和整体组织张力的变化，这两者都是神经管折叠所必需的，这表明以前未被认识到的NTD原因。这些力的动力学，组织流变特性，以及它们与细胞和遗传过程的相互作用是未知的。在此，结合定量组织力学和成像，我建议1)系统地绘制鸟类神经管和邻近组织的组织力学和细胞及细胞外基质组织；2)阐明平面细胞极性和叶酸通路在神经折叠过程中组织间力学中的作用；3)明确控制神经管腔形成和压力的细胞机制。我们的见解将改变我们对NTDs和更广泛的上皮形态发生机制的理解。我们的定量平台将广泛应用于其他形态发生模型，包括人类类器官。

项目成果

Cell density couples tissue mechanics to control the elongation speed of the body axis

细胞密度耦合组织力学来控制体轴的伸长速度

• DOI: 10.1101/2023.12.31.573670
• 发表时间: 2024
• 作者: Lu C

Differential tissue deformability underlies shape divergence of the embryonic brain and spinal cord under fluid pressure

不同的组织变形能力是流体压力下胚胎脑和脊髓形状差异的基础

• DOI: 10.1101/2024.01.12.575349
• 发表时间: 2024
• 作者: McLaren S