Regulatory Mechanisms Governing Precision in Vertebral Segmentation

控制椎体分割精度的调节机制

• 批准号: 10406991
• 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/10406991
• 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; Science; Segmentation Clock Pathway; Signal Transduction; Somites; Statistical Models; Stochastic Processes; System; Tail; Time; Tretinoin; cell growth; dosage; gene regulatory network; 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.

项目总结/摘要 及时和精确的进展遗传程序沿着级联的监管步骤是至关重要的， 执行一个发展过程。然而，基因表达是一个高度随机的过程， 复杂的生化反应动力学的波动;这种随机性导致大量的细胞间 基因表达噪音（Gene Expression Noise）由此产生的表型波动只能在 同基因群体中的单细胞水平。科学中最有趣的问题之一是 发展模式的形成是如此精确和可重复地执行，尽管这些不可避免的 基因表达的波动。据推测，缓冲随机基因表达的机制一定存在。 脊椎动物的体节发生为研究这一问题提供了一个范例系统。体节（Somite segments） 椎骨的胚胎前体）是从有丝分裂前的中胚层顺序地和周期性地产生的 (PSM)在胚胎的尾端体节分裂的周期受体节分裂的控制 时钟分割时钟表现出Hes/her家族“时钟”基因的振荡表达，这是由于 自抑制性细胞内负反馈环。振荡δ配体激活Notch受体， 并建立细胞间的正反馈回路， 相邻的细胞。这些同步振荡的中断会导致出生缺陷。的时间进程 体节的分裂和上皮化沿着后前方向进行。的 多个基因沿着PSM的协调表达由三个相互关联的信号传导控制 梯度（Fgf、Wnt和视黄酸）。体细胞发生是精确的--特定物种的胚胎发育 一定数量的片段与物种特异性的节奏-和多才多艺-总数量的片段和 它们的周期性在物种之间差异很大。体细胞发生也是稳健的，因为胚胎形成具有 一定的大小分布，缩放身体大小的片段的大小，甚至当总细胞数，细胞大小 或者生长速率通过实验改变。这些特征表明， 振荡分段网络被有效地缓冲。 我们的首要目标是破译基因调控网络中的表达噪音是如何缓冲的， 发展模式形成我们渴望通过以下方式对这种缓冲进行机械性理解 将数学/计算/统计建模与不同的遗传和化学扰动相结合， 改变多个基因的剂量或调节信号反馈强度。