Mechanics of Vertebrate Embryo Elongation

脊椎动物胚胎伸长的​​力学

• 批准号: 9766342
• 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/9766342
• 关键词: 4D Imaging; Automobile Driving; Behavior; Biological; Biomechanics; Birds; Body part; Cancer Biology; Cells; Chickens; Computer Simulation; 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; Stem cells; 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; 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.

项目摘要/摘要 身体的后部是由称为尾芽（TB）的结构逐渐形成的。缺陷 这一过程导致严重的先天缺陷，例如脊柱裂或尾骨。进步 后体的伸长需要控制结核病回归的力和 祖细胞的持续供应产生形成组织。在以前的工作中，我们已经证明 在鸡胚胎中，从结核病驱动身体伸长的过程涉及后部 前中胚层（PSM），其中细胞建立了随机细胞运动的梯度（细胞扩散） FGF信号的下游（Benazeraf等，2010）。 与我们的Co-Pi Mahadevan一起，我们详细阐述了一个新的物理框架，建议 细胞扩散的梯度起作用是产生与伸长运动有关的力 暴露于温度梯度的气体颗粒会产生压力（Regev等，2017）。我们的 模型基于最小数量的参数：细胞扩散梯度，添加细胞的速率 PSM和组织机械电阻，导致单向伸长力。在这里，我们会的 通过结合发育生物学，成像和软物质在体内测量这些参数 物理方法的目的是预测胚胎伸长率随空间的函数 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 在其体内形成的情况下，使用时间流逝成像和扰动策略。我们还将使用 胚胎中的生物物理方法直接测试PSM中的细胞扩散梯度是否为 能够产生负责轴伸长的力。我们将利用软性 物理方法来表征构成重要的PSM的流变特性 物理模型的要素。 模型的一个重要参数是TB的细胞添加速率，允许持续 在胚胎发育过程中看到的伸长运动。我们将在鸡肉中使用4D成像，然后 鹌鹑转基因胚胎以量化细胞从结核病到后PSM的流动。 最后，我们建议探索伸长配位的细胞和机械方面 在包含PSM前体的轴向结核区域和形成后PSM之间 了解后PSM如何向后推进结核。 该提案的发现应导致对后部形成的深入了解 组织，脊椎动物发育的研究。这项工作将具有重要的影响 为了理解诸如尾骨回归综合征和再生医学之类的先天缺陷。