Integration of spatiotemporal signaling for pattern formation and scaling

整合时空信号以形成模式和缩放

• 批准号: 10489850
• 负责人: Ertugrul M Ozbudak
• 金额: $ 44.76万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10489850
• 关键词: 3-Dimensional; Actins; Address; Anterior; BHLH Protein; Binding; Cell Nucleus; Cell Polarity; Cells; Characteristics; Chick; Clock protein; Complex; Computer Models; Congenital Abnormality; Cytoskeleton; Data; Data Analyses; Defect; Development; Diffusion; Disease; Dynein ATPase; Embryo; Embryonic Development; Ensure; Etiology; FGF17 gene; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Fishes; Future; Gene Family; Generations; Homeostasis; Image; Investigation; Length; Ligands; Longevity; Malignant Neoplasms; Measures; Mediating; Mesoderm; Messenger RNA; Microtubule-Organizing Center; Microtubules; Mission; Modeling; Mosaicism; Mus; Myosin ATPase; Nuclear; Organ; Organoids; Pattern; Pattern Formation; Phosphoric Monoester Hydrolases; Positioning Attribute; Process; Proteins; Reporter; Role; Rotation; Segmentation Clock Pathway; Signal Transduction; Site; Somites; Source; Syndrome; Testing; Time; Tissues; Transcription Repressor; United States National Institutes of Health; Update; Work; Zebrafish; base; cancer type; experimental study; genetic regulatory protein; heparin proteoglycan; inhibitor; loss of function; malformation; mathematical model; novel; real-time images; single molecule; spatiotemporal; spine bone structure

Abstract Tissues and organs display characteristic patterns established during embryonic development. Segmentation of somites, precursors of vertebrae, is a unique example in which spatial patterns are established sequentially and periodically. The prevailing clock and wavefront (CW) model states that the period of segmentation is set by the oscillatory expression of the Hes/her gene family (the segmentation clock). Disrupting these oscillations causes vertebral defects. The CW model further states that the positions of segment boundaries are determined by a critical readout of a signaling gradient (i.e. the wavefront) in the middle of the presomitic mesoderm (PSM). Depending on the stage, three to five compartments are predetermined to segment. We recently developed a novel 3D explant culture of zebrafish PSM and discovered that the FGF-mediated double phosphorylated ERK (ppERK) gradient is the wavefront. We also showed that in three popular vertebrate models (fish, chick and mice), anterior somite lengths are uniform but posterior somite lengths scale with the length of PSM. This scaling phenomenon contributes to the generation of species-specific segment numbers. Several important questions remain unsolved: 1) What mechanism controls segment length scaling, 2) How the clock and ppERK gradient are integrated to govern segmentation, and 3) How cells decode the spatiotemporal information, provided by the clock and ppERK gradient, to commit to segmentation in mid-PSM. To address these fundamental questions, we will perturb the clock, gradient or cell polarity machinery in a spatiotemporally-controlled manner, visualize their readouts at the single-cell level, and combine quantitative data analysis with mathematical modeling to test alternative mechanistic hypotheses: Aim 1: Discover the mechanism governing pattern size scaling. Aim 2: Discover the mechanism integrating the segmentation clock with the wavefront. Aim 3: Discover the mechanism decoding spatiotemporal information of the clock and wavefront. Hes/Her oscillations and FGF/ERK activity control pattern formation in various tissues during development. Disruption of their activities also result in specific cancer types. Our work might inspire future investigations on their roles during development of other tissues and how their dysregulations result in birth defects and cancer. Therefore, this application has strong relevance to the mission of the National Institute of Health.

摘要 组织和器官显示在胚胎发育过程中形成的特征模式。分割 体节是脊椎骨的前驱，是一个独特的例子，其中空间模式是按顺序建立的 而且是周期性的。主流时钟和波前(CW)模型说明分段周期已设置 通过Hes/Her基因家族(分段时钟)的振荡表达。扰乱这些振荡 会导致脊椎缺陷。CW模型还指出，分段边界的位置是 由信号梯度(即波前)的关键读数确定 中胚层(PSM)。根据舞台的不同，预先确定了三到五个隔室来分割。我们 最近发展了一种新的斑马鱼PSM的3D外植体培养，并发现成纤维细胞生长因子介导的双重 磷酸化ERK(PpERK)梯度是波前。我们还发现，在三种常见的脊椎动物中 模型(鱼、鸡和小鼠)的前体节长度是一致的，但后体节长度随 PSM的长度。这种伸缩现象有助于物种特定节段编号的产生。 几个重要的问题仍然没有解决：1)什么机制控制数据段长度缩放，2)如何 时钟和ppERK梯度被集成以管理分段，以及3)细胞如何解码 由时钟和ppERK梯度提供的时空信息，用于PSM中期的分割。 为了解决这些基本问题，我们将扰乱时钟、梯度或细胞极性机制 时空可控的方式，在单细胞水平上可视化他们的读数，并结合定量 使用数学建模进行数据分析，以测试可选的机械假设：目标1：发现 控制图案大小缩放的机制。目标2：发现分段时钟的整合机制 用波阵面。目标3：发现时钟时空信息的解码机制，并 波前。不同组织中HES/HER振荡和成纤维细胞生长因子/ERK活性调控模式的形成 发展。它们活动的中断也会导致特定的癌症类型。我们的工作可能会启发未来 它们在其他组织发育中的作用及其失调如何导致生育的研究 缺陷和癌症。因此，这项申请与美国国家科学研究院的使命有很强的相关性。 健康。