Illuminating the chemical biology of stem cell decisions in plant roots

项目摘要 小分子对多细胞生物体中干细胞行为的适当调控至关重要。因此， 这些化合物的生物合成、感知或新陈代谢方面的缺陷可导致发育 异常和疾病。尽管小分子至关重要，但我们的绝大多数人 对它们功能的理解是通过间接测量得出的。通常，对小分子的研究 生物学仅限于遗传或生化方法，这些方法将功能作用归因于基于 与这些分子相互作用的基因或蛋白质的性质。或者，小分子是 使用化学分析方法进行研究，这种方法使大块组织均质，并破坏 信号。高分辨率的空间信息在发育中至关重要，干细胞通常由一个小的 组织的一小部分。为了更深入地研究干细胞行为的化学调控，我的实验室将 将能够直接测量小分子的局域和活性的技术应用于 他们的原生发展背景。这项工作将使用植物的根来完成，植物根是一种强大的 发展系统。根将所有的干细胞储存在根尖，这会产生一种发育 可在单个组织切片中检查的梯度。我的实验室将利用这种梯度来调查 小分子在干细胞决策中的作用。我们将使用MASS绘制植物根的发育化学图谱 使用合成荧光剂对小分子与蛋白质的相互作用进行光谱成像和可视化 记者。代谢产物驱动的发育机制将通过研究柠檬酸盐和 视黄醛，两种高度保守的代谢物，在根干细胞分裂和鉴定中具有新的作用。这 研究将产生：1)高空间分辨率的地图集，详细描述干细胞决定的化学特征， 从再生到分化2)对促进抗逆性细胞增殖途径的新见解 干细胞亚群和3)调控干细胞的动态代谢物驱动的信号通路的阐明 细胞构图。我们的初步结果表明，有许多小分子具有重要的 有待发现的发育角色。在化学和化学的交叉点进行研究 发育生物学将提供对干细胞决定的机械性洞察，这是不可能使用 单一学科的方法。因此，这项工作将丰富我们对保守和 管理干细胞模式、维持、分裂和命运获取的不同原则。 项目摘要/摘要第6页

Project Summary Small molecules are critical for proper regulation of stem cell behavior in multicellular organisms. Consequently, defects in the biosynthesis, perception, or metabolism of these compounds can cause developmental abnormalities and disease. Despite the critical importance of small molecules, the vast majority of our understanding of their functions is derived from indirect measurements. Typically, studies of small molecule biology are limited to genetic or biochemical approaches that ascribe functional roles to compounds based on the properties of the genes or proteins that interact with these molecules. Alternatively, small molecules are studied using chemical analysis approaches that homogenize bulk tissue and destroy the native context of the signals. High-resolution spatial information is critical in development, where stem cells often comprise a small fraction of the tissue. To enable deeper investigations of chemical regulation of stem cell behavior, my lab will apply technologies capable of directly measuring the localization and activity of small molecules in their native developmental contexts. This work will be done using plant roots, which are a powerful developmental system. Roots store all of their stem cells at the root tip, which generates a developmental gradient that can be examined in a single slice of tissue. My lab will leverage this gradient to investigate the role of small molecules in stem cell decisions. We will map the developmental chemistry of plant roots using mass spectrometry imaging and visualize small molecule interactions with proteins using a synthetic fluorogenic reporter. Metabolite-driven developmental mechanisms will be explored in depth by investigating citrate and retinaldehyde, two highly conserved metabolites with novel roles in root stem cell divisions and identity. This research will generate: 1) high-spatial resolution atlases detailing the chemical profiles of stem cell decisions, from regeneration to differentiation 2) novel insight into pathways that promote proliferation in stress-resilient stem cell subpopulations and 3) elucidation of dynamic metabolite-driven signaling pathways that regulate stem cell patterning. Our preliminary results suggest that there are many small molecules with important developmental roles that await discovery. Conducting research at the intersection of chemistry and developmental biology will provide mechanistic insight into stem cell decisions that would not be possible using a single-disciplinary approach. Accordingly, this work will enrich our understanding of the conserved and divergent principles that govern stem cell patterning, maintenance, divisions, and fate acquisition. Project Summary/Abstract Page 6