Regulatory Mechanisms Governing Precision in Vertebral Segmentation

控制椎体分割精度的调节机制

• 批准号: 10162773
• 负责人: Ertugrul M Ozbudak
• 金额: $ 51.68万
• 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: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10162773
• 关键词: Biochemical Reaction; Body Size; Buffers; Cell Count; Cell Size; Cells; Characteristics; Chemicals; Complex; Congenital Abnormality; Development; Developmental Process; Due Process; Embryo; Exhibits; Family; Feedback; Gene Expression; Genes; Genetic; Goals; Kinetics; Ligands; Mathematics; Mesoderm; Noise; Pattern Formation; Periodicity; Phase; Phenotype; Population; Regulator Genes; Science; Segmentation Clock Pathway; Signal Transduction; Somites; Statistical Models; Stochastic Processes; System; Tail; Time; Tretinoin; cell growth; dosage; malformation; notch protein; prevent; programs; somitogenesis; spine bone structure; transcriptome

PROJECT SUMMARY/ABSTRACT The timely and precise progression of a genetic program along a cascade of regulatory steps is critical to execute a developmental process. However, gene expression is a highly stochastic process due to inevitable fluctuations in the kinetics of complex biochemical reactions; this randomness leads to substantial cell-to-cell variability (gene expression noise). The resulting phenotypic fluctuations can only be detected and quantified at the single cell level within isogenic populations. One of the most intriguing questions in science is how developmental pattern formation is executed so precisely and reproducibly despite these unavoidable fluctuations in gene expression. Presumably, mechanisms that buffer stochastic gene expression must exist. Vertebrate somitogenesis provides a paradigm system for studying this question. Somite segments (the embryonic precursors of vertebrae) are produced sequentially and periodically from the presomitic mesoderm (PSM) at the tail end of the embryo. The period of somite segmentation is controlled by the segmentation clock. The segmentation clock exhibits oscillatory expression of Hes/her-family “clock” genes due to an autoinhibitory intracellular negative feedback loop. Oscillating Delta ligands activate Notch receptors in neighboring cells and establish an intercellular positive feedback loop that synchronizes oscillation phases among neighboring cells. Disruption of these synchronized oscillations results in birth defects. The time-course of somite segmentation and epithelization occur along the posteroanterior direction in the PSM. The coordinated expression of multiple genes along the PSM are controlled by three interconnected signaling gradients (Fgf, Wnt and retinoic acid). Somitogenesis is both precise – embryos of a given species develop certain number of segments with species-specific rhythmicity – and versatile –total number of segments and their periodicity vary widely among species. Somitogenesis is also robust as embryos form segments with a certain size distribution, scaling the sizes of segments with body size, even when total cell numbers, cell sizes or growth rates are altered experimentally. These characteristics indicate that the expression noise within the oscillating segmentation network is efficiently buffered. Our overarching goal is to decipher how expression noise in gene regulatory networks is buffered during developmental pattern formation. We aspire to reach a mechanistic understanding of this buffering by combining mathematical/computational/statistical modeling with different genetic and chemical perturbations to modify dosage of multiple genes or modulate signal feedback strength.

项目概要/摘要 遗传程序沿着一系列监管步骤及时、精确地进展对于 执行一个发展过程。然而，由于不可避免的因素，基因表达是一个高度随机的过程。 复杂生化反应动力学的波动；这种随机性导致大量的细胞间 变异性（基因表达噪音）。由此产生的表型波动只能在 等基因群体内的单细胞水平。科学中最有趣的问题之一是如何 尽管存在这些不可避免的问题，但发育模式的形成却如此精确且可重复地执行 基因表达的波动。据推测，缓冲随机基因表达的机制必定存在。 脊椎动物的体节发生为研究这个问题提供了一个范式系统。体节节段（ 椎骨的胚胎前体）是从前体中胚层顺序且周期性地产生的 （PSM）位于胚胎的尾部。体节分割的周期由分割控制 钟。分段时钟表现出 Hes/her 家族“时钟”基因的振荡表达，这是由于 自抑制细胞内负反馈环路。振荡 Delta 配体激活 Notch 受体 相邻细胞并建立同步振荡相位的细胞间正反馈回路 相邻小区之间。这些同步振荡的破坏会导致出生缺陷。时间进程 体节分割和上皮化沿着 PSM 的后前方向发生。这 多个基因沿着 PSM 的协调表达由三个相互关联的信号控制 梯度（Fgf、Wnt 和视黄酸）。体节发生是精确的——特定物种的胚胎发育 一定数量的具有物种特异性节律性的片段 - 和通用性 - 片段总数和 它们的周期性在物种之间差异很大。体节发生也很强大，因为胚胎形成具有 一定的尺寸分布，根据身体尺寸缩放片段的尺寸，即使总细胞数、细胞尺寸 或者通过实验改变增长率。这些特征表明，表达噪声内 振荡分段网络得到有效缓冲。 我们的首要目标是破译基因调控网络中的表达噪声在 发展格局的形成。我们渴望通过以下方式对这种缓冲达成机械理解 将数学/计算/统计模型与不同的遗传和化学扰动相结合 修改多个基因的剂量或调节信号反馈强度。