Mechanisms and developmental functions of cytoplasmic flows in early embryogenesis

早期胚胎发生中细胞质流动的机制和发育功能

基本信息

批准号：
10491186
负责人：
Stefano Di Talia
金额：
$ 28.89万
依托单位：
DUKE UNIVERSITY
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：
2021-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491186
关键词：
Actomyosin Address Affect Anterior Apical Biochemical Biological Biological Process Biophysics Blastoderm CDC2 gene Cell Cycle Cell Cycle Regulation Cell Nucleus Cells Characteristics Chemical Models Complex Computing Methodologies Coupling Cullin 5 Protein Cytoplasm Cytoplasmic streaming Cytoskeleton Cytosol Data Development Diffusion Drosophila genus Embryo Embryonic Development Ensure Epithelial Event Feedback Fertilization Gel Generations Genes Genetic Genetic Diseases Geometry Giant Cells Goals Human Lead Link Liquid substance Location Mammals Measures Mechanics Methodology Methods Mitotic Modeling Molecular Morphogenesis Nature Normal Cell Nuclear Outcome Pattern Play Positioning Attribute Process Property Protein phosphatase Proteins Role Signal Transduction System Temperature Testing Time Tissues Transgenic Organisms Work biological systems biophysical model blastomere structure constriction experimental study in vivo insight mathematical model mechanical signal morphogens mutant novel optogenetics organ growth physical process physical property programs quantitative imaging spatiotemporal ubiquitin ligase

项目摘要

Abstract The integration of biochemical and mechanical signals is an important and ubiquitous feature of biological systems. During embryonic development, this integration is required for complex tissue organization and function. We have recently shown that during the early, pre-blastoderm stages of Drosophila embryogenesis the integrated activities of the cell cycle oscillator and actomyosin contractility generate a self-organized mechanism of nuclear positioning which is essential for synchronization of the cell cycle. At the core of this mechanism are cytoplasmic flows that are initiated by cortical contractions. These, in turn, are linked spatiotemporally to the oscillation of mitotic Cyclin-dependent kinase 1 (Cdk1) and protein phosphatase 1 (PP1). These flows are able to transport nuclei and are responsible for their accurate positioning across the embryo. The goal of this proposal is to build on these novel findings and to understand more deeply the mechanisms and developmental functions of cytoplasmic flows. We will take three approaches to address these fundamental questions. 1. We will build a biophysical model that captures the coupling of biochemical and mechanical signals and the effective physical properties of the cytoplasm. The coupling between the cytoskeleton and the cytosol will be modeled by a two- fluid model: an active contractile gel and a viscous cytosol. 2. We will use genetic and optogenetics approaches to alter cortical contractility as well as transgenic approaches to change the geometry of the embryo and a novel setup to control temperature. These experiments will provide a novel paradigm for understanding the molecular mechanisms underlying the generation and the properties of cytoplasmic flows. 3. We will test whether cytoplasmic flows play a role in the formation of morphogen gradients. Specifically, we will use quantitative imaging and mathematical modeling to determine whether cytoplasmic flows affect the formation of the anterior- posterior gradient of Bicoid morphogen in the syncytial Drosophila embryo. Taken together these studies will provide a new paradigm for the integration of biochemical and mechanical signals that is likely to have general relevance for other developmental systems.

抽象的生化和机械信号的整合是生物化学的一个重要且普遍的特征在胚胎发育过程中，这种整合对于复杂的组织组织和发育是必需的。我们最近表明，在果蝇胚胎发生的早期、前胚层阶段，细胞周期振荡器和肌动球蛋白收缩性的综合活动产生自组织机制该机制的核心是核定位。由皮质收缩引发的细胞质流动反过来又与时空相关。有丝分裂细胞周期蛋白依赖性激酶 1 (Cdk1) 和蛋白磷酸酶 1 (PP1) 的振荡。这些流动是能够的。运输细胞核并负责其在胚胎中的准确定位。该提案的目标。就是要以这些新颖的发现为基础，更深入地了解其机制和发育功能细胞质流。我们将采取三种方法来解决这些基本问题。1.我们将建立一个生物物理模型，捕获生化和机械信号的耦合以及有效的物理信号细胞质的特性将通过二元模型来模拟。流体模型：活性收缩凝胶和粘性细胞质。2.我们将使用遗传和光遗传学方法改变皮质收缩性以及改变胚胎几何形状的转基因方法和一种新颖的方法这些实验将为理解分子提供一个新的范例。细胞质流的产生和特性的机制 3. 我们将测试是否。具体而言，细胞质流在形态发生素梯度的形成中发挥作用，我们将使用定量。成像和数学模型以确定细胞质流动是否影响前壁的形成合胞体果蝇胚胎中 Bicoid 形态发生素的后梯度为生化和机械信号的整合提供了一个新的范式，该范式可能具有通用性与其他发展系统的相关性。