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.

项目概要/摘要 身体的后部逐渐由称为尾芽（TB）的结构形成。缺陷于 这一过程会导致严重的出生缺陷，例如脊柱裂或尾骨发育不全。进步者 后体的伸长需要产生控制结核消退的力和 持续供应祖细胞来生成正在形成的组织。在之前的工作中，我们已经证明了 在鸡胚中，驱动身体从 TB 伸长的过程涉及后部 前成体中胚层 (PSM)，其中细胞建立随机细胞运动梯度（细胞扩散） FGF 信号传导的下游（Benazeraf 等，2010）。 我们与我们的联合 PI Mahadevan 一起制定了一个新的物理框架，建议： 细胞扩散的梯度产生参与伸长运动的力，就像 暴露在温度梯度下的气体粒子会产生压力（Regev 等人，2017）。我们的 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、成像和软物质在体内测量这些参数 物理学方法的目标是预测作为空间函数的胚胎伸长率 和时间。 我们首先提出研究细胞扩散梯度的细胞基础和 FGF 信号传导的作用 使用延时成像和微扰策略在体内形成它。我们还将使用 在胚胎中采用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 物理方法来表征 PSM 的流变特性，这构成了重要的 物理模型的元素。 模型的一个重要参数是来自 TB 的细胞添加速率，该速率允许持续 胚胎发育过程中观察到的伸长运动。我们将在鸡和 鹌鹑转基因胚胎来量化细胞从 TB 到后 PSM 的流动。 最后，我们建议探索伸长协调的细胞和机械方面 包含 PSM 前体的轴向 TB 区域和正在形成的后 PSM 之间，以尝试 了解后 PSM 如何向后推动 TB。 该提案的研究结果应有助于深入了解后验的形成 组织，脊椎动物发育的一个尚未得到充分研究的方面。这项工作将产生重要影响 用于了解出生缺陷（例如尾部退化综合症）和再生医学。