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期间建立的特征模式。分割 体节，椎骨的前体，是一个独特的例子，其中空间模式建立顺序 并且周期性地。流行的时钟和波前（CW）模型指出，分割的周期被设置为 通过Hes/her基因家族的振荡表达（分段时钟）。扰乱这些振荡 导致脊椎缺损CW模型进一步指出，段边界的位置是 通过在分裂前中间的信号梯度（即波前）的临界读数来确定 中胚层（PSM）。根据阶段，三到五个隔间被预先确定为分段。我们 最近开发了一种新的斑马鱼PSM的3D外植体培养物，发现FGF介导的双 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），前体节长度是均匀的，但后体节长度与 PSM长度。这种缩放现象有助于产生物种特异性片段数。 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梯度被整合以管理分割，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，并将联合收割机定量 数据分析与数学建模测试替代机制假设：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 波阵面目标3：揭示时钟时空信息的解码机制， 波前Hes/Her振荡和FGF/ERK活性控制各种组织中的模式形成， 发展破坏它们的活动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，本申请与国家生物技术研究所的使命具有很强的相关性。 健康