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 身体的后部由一种叫做尾芽(TB)的结构逐渐形成。中的缺陷 这一过程会导致严重的出生缺陷，如脊柱裂或尾部发育不全。进步者 后半身的伸长需要产生控制结核消退的力量和 持续供应祖细胞以生成形成组织。在以前的工作中，我们已经证明 在鸡胚胎中，从结核驱动身体伸长的过程涉及后部 分裂前中胚层(PSM)，其中细胞建立随机细胞运动的梯度(细胞扩散) 成纤维细胞生长因子信号的下游(Benazeraf等人，2010年)。 与我们的合作者Pi Mahadean一起，我们制定了一个新的物理框架，提出 细胞扩散的梯度作用于产生牵涉到伸长运动的力，很像 暴露在温度梯度下的气体颗粒产生压力(Regev等人，2017)。我们的 模型基于最小数量的参数：细胞扩散梯度、细胞添加速率 PSM和组织的机械阻力，导致单向拉伸力。在这里，我们将 结合发育生物学、成像和软物质在活体内测量这些参数 物理学的目标是预测胚胎的伸长率作为空间的函数 还有时间。 我们首先提出要研究细胞扩散梯度的细胞基础和成纤维细胞生长因子信号的作用。 利用时间推移成像和微扰策略在体内形成它。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 能够产生导致轴伸长的力。我们将利用软物质 表征PSM流变性的物理方法，这是重要的 物理模型的元素。 模型的一个重要参数是结核细胞的添加速率，该速率允许持续的 胚胎发育过程中可见的伸长运动。我们将在鸡身上使用4D成像技术， 以量化从TB到PSM后部的细胞流动情况。 最后，我们建议探索细胞和力学方面的协调伸长 在含有PSM前体轴向结核区域和形成后PSM区域之间尝试 了解后方PSM如何将结核推向后方。 这一建议的发现应该有助于对后部形成的深入理解 组织，脊椎动物发育的一个未被充分研究的方面。这项工作将具有重要的意义 用于了解出生缺陷，如尾部退化综合征和再生医学。