Integration of spatiotemporal signaling for pattern formation and scaling

整合时空信号以形成模式和缩放

基本信息

批准号：
10656503
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
项目类别：
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/10656503
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 Genetic Transcription Homeostasis Image Investigation Length Ligands Longevity Malignant Neoplasms Measures Mediating Mesoderm Messenger RNA Microtubule-Organizing Center Microtubules Mission Modeling Mus Myosin ATPase Nuclear Organ Organoids Pattern Pattern Formation Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Inhibition 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 Visualization Work Zebrafish cancer type experimental study genetic regulatory protein heparin proteoglycan inhibitor loss of function malformation mathematical model mosaic loss novel real-time images single molecule spatiotemporal spine bone structure

项目摘要

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在胚胎发育过程中建立的特征模式。分割椎骨的前体的物种是一个独特的例子，在其中依次建立空间模式并定期。盛行的时钟和波前（CW）模型指出，设置了分割周期通过HES/她的基因家族的振荡表达（分割时钟）。破坏这些振荡导致椎骨缺陷。 CW模型进一步指出，段边界的位置是由信号传导梯度（即波前）的临界读数确定中胚层（PSM）。根据阶段，预定了三到五个隔室。我们最近开发了一种新颖的斑马鱼PSM的3D外植体培养物，发现FGF介导的双重磷酸化ERK（PPERK）梯度是波前。我们还表明，在三个流行的脊椎动物中模型（鱼，小鸡和小鼠），前节长度均匀，但后部长度尺寸为 PSM的长度。这种缩放现象有助于物种特异性段数的产生。几个重要问题仍未解决：1）哪些机制控制段长度缩放，2）时钟和pperk梯度被整合到控制分段，3）细胞如何解码时钟和PPERK梯度提供的时空信息，以在PSM中进行分割。为了解决这些基本问题，我们将在一个时钟，梯度或细胞极性机械上扰动时空控制的方式，在单细胞水平上可视化其读数，然后结合定量使用数学建模的数据分析以检验替代机械假设：目标1：发现控制图案尺寸缩放的机制。目标2：发现整合分段时钟的机制与波前。目标3：发现时钟时时空信息的机制波前。 HES/她的振荡和FGF/ERK活性控制模式在各种组织中形成发展。其活动的破坏也导致特定的癌症类型。我们的工作可能会激发未来调查其在其他组织开发过程中的作用以及其失调如何导致出生缺陷和癌症。因此，该申请与国家研究所的使命有很强的意义健康。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A design logic for sequential segmentation across organisms.

跨生物体顺序分割的设计逻辑。

DOI：
10.1111/febs.16899
发表时间：
2023
期刊：
The FEBS journal
影响因子：
0
作者：
Simsek,MFethullah;Özbudak,ErtuğrulM
通讯作者：
Özbudak,ErtuğrulM

Patterning principles of morphogen gradients.

DOI：
10.1098/rsob.220224
发表时间：
2022-10
期刊：
Open biology
影响因子：
5.8
作者：
通讯作者：

Spatiotemporal control of pattern formation during somitogenesis.

DOI：
10.1126/sciadv.adk8937
发表时间：
2024-01-26
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Mcdaniel, Cassandra;Simsek, M. Fethullah;Chandel, Angad Singh;Ozbudak, Ertugrul M.
通讯作者：
Ozbudak, Ertugrul M.

Periodic inhibition of Erk activity drives sequential somite segmentation.

DOI：
10.1038/s41586-022-05527-x
发表时间：
2023-01
期刊：
NATURE
影响因子：
64.8
作者：
Simsek, M. Fethullah;Chandel, Angad Singh;Saparov, Didar;Zinani, Oriana Q. H.;Clason, Nicholas;Ozbudak, Ertugrul M.
通讯作者：
Ozbudak, Ertugrul M.