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.

抽象的 组织和器官显示出胚胎发育过程中建立的特征模式。分割 体节（椎骨的前身）的组成是一个独特的例子，其中空间模式是按顺序建立的 并定期。流行的时钟和波前 (CW) 模型表明分段周期已设置 通过 Hes/her 基因家族的振荡表达（分段时钟）。破坏这些振荡 导致脊椎缺陷。 CW 模型进一步指出，段边界的位置是 由前体中间的信号梯度（即波前）的临界读数确定 中胚层（PSM）。根据阶段的不同，预先确定三到五个隔室进行分割。我们 最近开发了一种新型斑马鱼 PSM 3D 外植体培养物，并发现 FGF 介导的双 磷酸化 ERK (ppERK) 梯度是波前。我们还表明，在三种流行的脊椎动物中 模型（鱼、小鸡和小鼠），前体节长度是均匀的，但后体节长度与 PSM 的长度。这种缩放现象有助于生成特定物种的片段编号。 几个重要问题仍未解决：1）什么机制控制段长度缩放，2）如何控制 时钟和 ppERK 梯度被集成来控制分割，以及 3) 细胞如何解码 由时钟和 ppERK 梯度提供的时空信息，用于在 PSM 中期进行分割。 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 时空控制的方式，在单细胞水平上可视化它们的读数，并结合定量 通过数学建模进行数据分析，以测试替代机制假设：目标 1：发现 控制图案尺寸缩放的机制。目标2：发现集成分段时钟的机制 与波前。目标3：发现时钟和时空信息的解码机制 波前。 Hes/Her 振荡和 FGF/ERK 活性控制不同组织中的模式形成 发展。它们的活动受到干扰也会导致特定的癌症类型。我们的工作可能会启发未来 研究它们在其他组织发育过程中的作用以及它们的失调如何导致出生 缺陷和癌症。因此，该应用程序与国家研究所的使命密切相关。 健康。