A Molecular Genetic Analysis of Root Morphogenesis

根形态发生的分子遗传学分析

• 批准号: 10598025
• 负责人: Philip N Benfey
• 金额: $ 30.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598025
• 关键词: Address; Animals; Arabidopsis; Biological Process; Cell division; Cells; Coupled; Daughter; Development; Developmental Biology; Disease; Ectopic Expression; Engineering; Heart; Image; Knowledge; Light; Logic; Maps; Microscopy; Modeling; Molecular; Molecular Genetics; Morphogenesis; Organism; Pathway interactions; Plants; Pluripotent Stem Cells; Process; Public Health; Regenerative Medicine; Regulation; Testing; Time; Tissue Differentiation; Work; developmental disease; genetic analysis; genome-wide; insight; mathematical model; neoplastic cell; network models; real-time images; regenerative treatment; stem cell population; stem cells; tissue regeneration; Address; Animals; Arabidopsis; Biological Process; Cell division; Cells; Coupled; Daughter; Development; Developmental Biology; Disease; Ectopic Expression; Engineering; Heart; Image; Knowledge; Light; Logic; Maps; Microscopy; Modeling; Molecular; Molecular Genetics; Morphogenesis; Organism; Pathway interactions; Plants; Pluripotent Stem Cells; Process; Public Health; Regenerative Medicine; Regulation; Testing; Time; Tissue Differentiation; Work; developmental disease; genetic analysis; genome-wide; insight; mathematical model; neoplastic cell; network models; real-time images; regenerative treatment; stem cell population; stem cells; tissue regeneration

A central question in developmental biology is, “How do cells progress from pluripotent stem cells to fully differentiated tissues.” Stem cells divide asymmetrically to give daughters that are launched on different trajectories. On each trajectory, cells pass through different states as they progress toward end-stage differentiation. There are surprisingly few cases in which this whole process has been mapped out and there are no cases in which the regulation of the entire process is understood. Answers to this question lie at the heart of regenerative medicine and treatment of developmental disorders. We address this question using the root of Arabidopsis as a tractable model. Comparing and contrasting pathways to differentiation in animals and plants allows us to understand their underlying logic, as these evolved completely independently. Our work has identified the core molecular network required for the division and differentiation of one stem cell population. Mathematical modeling of this network generated hypotheses as to how it functions. We are now experimentally testing those hypotheses as well as imaging network dynamics in real time. We have also identified key regulators of differentiation in this lineage. Ectopic expression of these regulators provided insights into the stability of cell fate and the requirements for acquiring cell fate. Our progress in characterizing the path from stem cell to differentiated tissue in the root will allow us to address fundamental questions including, “How are formative asymmetric cell divisions regulated?” and “What controls differentiation?” To address these questions, we will use real time imaging with light sheet microscopy during asymmetric cell divisions and single-cell genome-wide expression analysis during the acquisition of cell fate. To fully understand the network motifs controlling these processes we will reengineer them using synthetic components. Observing network dynamics in a multicellular organism is a unique approach and has the potential to inform basic questions regarding network function in other biological processes. Generating synthetic network motifs coupled with mathematical modeling will provide key insights into the logic of regulatory networks that control development as well as into disease processes that disrupt them.

发育生物学中的一个核心问题是：“细胞如何从多功能中发展 干细胞到完全分化的组织。”干细胞不对称地分裂 在不同轨迹上发射的女儿。在每个轨迹上，细胞通过 通过不同的状态朝着终点分化迈进。有 令人惊讶的是，很少有整个过程被绘制出来的情况，并且 没有理解整个过程的调节的情况。答案 问题是再生医学的核心和发展的核心 疾病。我们使用拟南芥作为可拖动模型来解决这个问题。 比较和对比的动物和植物分化途径使我们 了解它们的基本逻辑，因为这些逻辑完全独立发展。我们的 工作已经确定了分区所需的核心分子网络和 一个干细胞种群的分化。该网络的数学建模 生成的假设是其运作方式。我们现在正在实验测试那些 实时假设以及成像网络动力学。我们还确定了 该血统中分化的关键调节因子。这些调节剂的异位表达 提供了有关细胞命运稳定性和征收细胞的要求的见解 命运。我们表征从干细胞到分化组织的路径的进展 根将使我们能够解决基本问题，包括：“形成如何 受调节的不对称细胞划分？”和“什么控制分化？”以解决 这些问题，我们将使用轻度显微镜进行实时成像 在此期间不对称细胞分裂和单细胞基因组表达分析 收集细胞命运。充分了解控制这些的网络主题 流程我们将使用合成组件对其进行重新设计。观察网络 多细胞生物中的动力学是一种独特的方法，有潜力 在其他生物过程中有关网络功能的基本问题。 生成合成网络图案加上数学建模将提供 对控制开发以及的监管网络逻辑的关键见解以及 进入破坏它们的疾病过程。