Tissue Mechanics in Neural Tube Morphogenesis

组织形态发生依赖于作用于组织软质属性的内力和外力。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，多种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仍不清楚。闭合失败会导致神经管缺陷(NTDS)，这是一种常见的发育异常，是世界范围内的健康负担。要解决神经管畸形的病因学，必须确定驱动神经管折叠的组织力量，并揭示它们的遗传和细胞起源和调节。鸟类神经管具有与人类相同的关键形态发生特征，同时提供了容易获得成像和机械工具的途径。最近，我和同事们开发了一种新型测力探头，用于直接测量和加载活体禽类胚胎的组织应力。重要的是，我们确定了来自发育前中胚层的压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，这表明以前未发现的NTD原因。这些力量的动态，组织流变性，以及它们与细胞和遗传过程的相互作用尚不清楚。在这里，我建议结合定量组织力学和成像，1)系统地绘制鸟类神经管和邻近组织的组织力学图和细胞及细胞外基质组织图；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)确定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的理解，更广泛地说，将改变我们对上皮形态发生机制的理解。我们的定量平台将在其他形态发生模型中有广泛的应用，包括人类器官。

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.