A Molecular Genetic Analysis of Root Morphogenesis

根形态发生的分子遗传学分析

• 批准号: 9902468
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902468
• 关键词: Address; Animals; Arabidopsis; Biological Process; Cell division; Cells; Coupled; Daughter; Development; Developmental Biology; Disease; Ectopic Expression; Heart; Image; Light; Logic; Maps; Microscopy; Modeling; Molecular; Molecular Genetics; Morphogenesis; Organism; Pathway interactions; Plant Roots; Plants; Pluripotent Stem Cells; Process; Public Health; Regenerative Medicine; Regulation; Testing; Time; Tissue Differentiation; Work; developmental disease; genetic analysis; genome-wide; health knowledge; insight; mathematical model; neoplastic cell; network models; real-time images; 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.

发育生物学的一个中心问题是，“细胞是如何从多能 从干细胞到完全分化的组织。”干细胞不对称分裂， 女儿们以不同的轨迹发射。在每个轨迹上，细胞通过 通过不同的状态向分化末期发展。有 令人惊讶的是，很少有这样的情况下，这整个过程已经绘制出来， 没有理解整个过程的调节的情况。的答案 问题在于再生医学和治疗发育 紊乱我们解决这个问题使用拟南芥根作为一个易处理的模型。 比较和对比动物和植物的分化途径使我们能够 理解它们的内在逻辑，因为它们是完全独立进化的。我们 工作已经确定了分裂所需的核心分子网络， 一个干细胞群体的分化。这个网络的数学模型 产生了关于它如何运作的假设。我们现在正在实验性地测试 假设以及真实的实时成像网络动态。我们还确定 分化的关键调节因子。这些调节因子的异位表达 提供了对细胞命运的稳定性和获得细胞的要求的见解， 命运我们在表征干细胞到分化组织的途径方面的进展， 根将使我们能够解决基本问题，包括，“如何形成 不对称细胞分裂受到调控“和“什么控制分化？”解决 这些问题，我们将使用真实的时间成像与光片显微镜在 不对称细胞分裂和单细胞全基因组表达分析， 获取细胞命运。为了充分理解控制这些的网络图案， 我们将使用合成组件对其进行重新设计。观测网络 在多细胞生物中的动力学是一种独特的方法，并有可能 提供关于其他生物过程中网络功能的基本问题。 生成与数学建模相结合的合成网络基序将提供 对控制发展的监管网络逻辑的关键见解， 转化为破坏它们的疾病过程。