Mechanics of Vertebrate Embryo Elongation

脊椎动物胚胎伸长的​​力学

• 批准号: 9912796
• 负责人: OLIVIER POURQUIE
• 金额: $ 54.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912796
• 关键词: 4D Imaging; Automobile Driving; Behavior; Biological; Biomechanics; Birds; Body part; Cancer Biology; Cells; Chickens; Computer Models; Congenital Abnormality; Data; Defect; Development; Developmental Biology; Diffusion; Elements; Embryo; Embryonic Development; Exposure to; Fibroblast Growth Factor; Gases; Generations; Goals; Growth; Image; Injections; Knowledge; Lead; Light; Limb structure; Logic; Measures; Mechanics; Mesoderm; Mesoderm Cell; Modeling; Molecular; Movement; Musculoskeletal; Neural tube; Paraxial Mesoderm; Physics; Process; Production; Property; Quail; Regenerative Medicine; Resistance; Rheology; Role; Sacral agenesis; Signal Transduction; Spinal Dysraphism; Structure; Tail; Techniques; Temperature; Testing; Time; Tissues; Transgenic Organisms; Work; base; biophysical techniques; cell motility; experimental study; in vivo; particle exposure; physical model; pressure; progenitor; stem cells; time use; vertebrate embryos

Project Summary/Abstract The posterior part of the body is progressively formed from a structure called tail bud (TB). Defects in this process lead to severe birth defects such as spina bifida or caudal agenesis. The progressive elongation of the posterior body requires the generation of forces controlling TB regression and a constant supply of progenitors to generate the forming tissues. In previous work, we have shown that in the chicken embryo the process driving body elongation from the TB involves the posterior presomitic mesoderm (PSM) where cells establish a gradient of random cell motility (cell diffusion) downstream of FGF signaling (Benazeraf et al, 2010). Together with our co-PI Mahadevan, we have elaborated a new physical framework proposing that the gradient of cell diffusion acts to generate forces involved in the elongation movements much like gas particles exposed to a gradient of temperature generate pressure (Regev et al, 2017). Our models are based on a minimal number of parameters: cell diffusion gradient, rate of cell addition to the PSM, and tissue mechanical resistance, leading to a unidirectional elongation force. Here, we will measure these parameters in vivo by combining developmental biology, imaging and soft matter physics approaches with the goal of predicting the rate of embryo elongation as a function of space and time. We first propose to study the cellular basis of the cell diffusion gradient and the role of FGF signaling in its formation in vivo using time lapse imaging and perturbation strategies. We will also use biophysical approaches in the embryo to directly test whether the cell diffusion gradient in the PSM is able to generate the forces responsible for axis elongation. We will take advantage of soft-matter physics approaches to characterize the rheological properties of the PSM which constitute important elements of the physical models. An important parameter of the models is the rate of cell addition from the TB that allows the sustained elongation movements seen during embryonic development. We will use 4D-imaging in chicken and quail transgenic embryos to quantify the flow of cells from the TB to the posterior PSM. Finally, we propose to explore the cellular and mechanical aspects of the coordination of elongation between the axial TB territory containing the PSM precursors and the forming posterior PSM to try to understand how the posterior PSM propels the TB posteriorly. The findings of this proposal should lead to an in-depth understanding of the formation of posterior tissues, an understudied aspect of vertebrate development. This work will have important implications for understanding birth defects such as caudal regression syndrome and for regenerative medicine.

项目总结/摘要 身体的后部由一个叫做尾芽（TB）的结构逐渐形成。缺陷 这一过程导致严重的出生缺陷，如脊柱裂或尾部发育不全。逐步 后体的伸长需要产生控制TB回归的力， 不断提供祖细胞以生成组织。在以前的工作中，我们已经表明， 在鸡胚胎中，驱动身体从TB延伸的过程涉及后部 有体前中胚层（PSM），其中细胞建立随机细胞运动梯度（细胞扩散） 在FGF信号传导的下游（Benazeraf等人，2010）。 与我们的合作PI Mahadevan一起，我们制定了一个新的物理框架， 细胞扩散的梯度产生了与伸长运动有关的力 暴露于温度梯度的气体颗粒产生压力（Regev等人，2017）。我们 模型基于最少数量的参数：细胞扩散梯度，细胞添加速率， PSM和组织机械阻力，导致单向伸长力。在这里，我们将 通过结合发育生物学、成像和软物质来测量这些参数 物理学方法，其目标是预测胚胎伸长的速率作为空间的函数 和时间 我们首先建议研究细胞扩散梯度的细胞基础和FGF信号的作用 在其体内形成使用时间推移成像和扰动策略。我们还将使用 在胚胎中的生物物理方法，以直接测试PSM中的细胞扩散梯度是否 能够产生导致轴伸长的力。我们将利用软物质 物理方法来表征PSM的流变特性， 物理模型的元素。 模型的一个重要参数是从TB添加细胞的速率，其允许持续的细胞增殖。 在胚胎发育过程中观察到的伸长运动。我们将在鸡肉中使用4D成像， 鹌鹑转基因胚胎，以量化从TB到后PSM的细胞流动。 最后，我们建议探讨细胞和机械方面的协调伸长 在包含PSM前体的轴向TB区域和形成的后PSM之间， 了解后部PSM如何向后推动结核病。 这一建议的发现应导致对后牙槽骨形成的深入了解。 组织，这是脊椎动物发育的一个未充分研究的方面。这项工作将具有重要意义 用于了解出生缺陷，如尾部退化综合征和再生医学。