Biomechanical mechanisms underlying the formation of the vertebrate body axis

项目摘要 将组织和器官雕刻成它们的3D功能形态需要严格的时空控制， 组织力学当细胞产生的机械力为形态发生提供动力时， 在3D中塑造胚胎组织在很大程度上取决于局部组织材料的特性，这决定了胚胎组织的形状。 系统对内部产生的力的响应。因此，两者的时空变化 机械力和材料性质可以独立地或组合地指导形态发生。的 到目前为止，在发育中的胚胎中探测组织力学的复杂性阻碍了我们解剖 他们的具体作用，更一般地说，了解支配3D组织的生物力学机制 和器官形态发生。 使用PI最近开发的基于微滴的新技术来测量组织材料 特性和内源性机械应力在发育中的胚胎，我们建议揭示 斑马鱼体轴形成的生物力学机制。在后体轴 在伸长时，细胞在其运动性中显示出前后梯度。我们的初步数据表明， 细胞运动中的前后变化可能是由细胞的流体样状态和细胞的细胞运动之间的过渡引起的。 在裂殖前中胚层中，后端的组织转变为固体状状态。我们的假设是 类流体和类固体组织状态的差异通过启用或限制 形态发生流具体来说，我们假设在斑马鱼身体伸长过程中， 中胚层从尾芽中的流体样行为转变为前体中胚层中的固体样行为， 允许组织在伸长的身体末端流动，同时为发育中的老年人提供机械完整性， 结构，从而引导身体轴的几乎单向的组织伸长。为了测试这种 假设，我们计划（1）测量和比较组织屈服应力的前后变化， 内源性机械应力，以建立在身体过程中流体样或固体样组织区域的存在 轴伸长，（2）建立关键功能分子（肌动蛋白，非肌肉肌球蛋白II和N-钙粘蛋白） 控制组织力学和类固体和类流体组织状态的梯度，以及（3）整合分子、细胞 和组织力学转化为身体伸长的多尺度生物力学模型。 我们相信这项研究将揭示3D组织和器官形态发生的新生物力学机制， 其中流体状和固体状组织区域的空间控制引导胚胎组织的成形。 此外，它将剖析3D组织中机械应力和材料特性的具体作用 形态发生和建立关键功能分子如何控制体内组织力学。!

PROJECT SUMMARY Sculpting tissues and organs into their 3D functional morphologies requires a tight spatiotemporal control of tissue mechanics. While cell-generated mechanical forces power morphogenesis, the resulting tissue flows that shape embryonic tissues in 3D depend strongly on the local tissue material properties, which govern the system's response to the internally generated forces. As a consequence, spatiotemporal variations in both mechanical forces and material properties can, independently or in combination, guide morphogenesis. The complexity of probing tissue mechanics within developing embryos has so far hindered our ability to dissect their specific roles and, more generally, to understand the biomechanical mechanisms that govern 3D tissue and organ morphogenesis. Using novel microdroplet-based techniques that the PI recently developed to measure both the tissue material properties and endogenous mechanical stresses within developing embryos, we propose to reveal the biomechanical mechanisms that underlie the formation of the zebrafish body axis. During posterior body axis elongation, cells display an anteroposterior gradient in their motility. Our preliminary data suggest that the anteroposterior variations in cellular movements may be caused by a transition between a fluid-like state of the tissue at the posterior end to a solid-like state in the presomitic mesoderm. Our hypothesis is that regional differences in fluid-like and solid-like tissue states control 3D tissue morphogenesis by enabling or restricting morphogenetic flows. Specifically, we hypothesize that during zebrafish body elongation the paraxial mesoderm transits from a fluid-like behavior in the tailbud to a solid-like behavior in the presomitic mesoderm, allowing tissue flows at the elongating body end while providing mechanical integrity to developmentally older structures, thereby guiding the nearly unidirectional tissue elongation of the body axis. In order to test this hypothesis, we plan to (1) measure and compare anteroposterior variations in tissue yield stress and endogenous mechanical stresses to establish the existence of fluid-like or solid-like tissue regions during body axis elongation, (2) establish how key functional molecules (actin, non-muscle myosin II and N-cadherin) control gradients in tissue mechanics and solid-like and fluid-like tissue states, and (3) integrate molecular, cell and tissue mechanics into a multiscale biomechanical model of body elongation. We believe this research will reveal a novel biomechanical mechanism of 3D tissue and organ morphogenesis, in which the spatial control of fluid-like and solid-like tissue regions guides the shaping of embryonic tissues. Moreover, it will dissect the specific roles of mechanical stresses and material properties in 3D tissue morphogenesis and establish how key functional molecules control tissue mechanics in vivo. !