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: 10295895
• 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/10295895
• 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/antagonist; 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