Beyond cell shape: Actin exerts systems-level control during morphogenesis
超越细胞形状:肌动蛋白在形态发生过程中发挥系统级控制
基本信息
- 批准号:8903452
- 负责人:
- 金额:$ 30.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsActomyosinAdultApicalBindingBiochemicalBiological AssayCell NucleusCell ShapeCell membraneCell surfaceCellsCongenital AbnormalityContractsCoupledCytokinesisCytoskeletonDataDevelopmentDiseaseDrosophila genusEmbryoEnsureEnvironmentEpithelialEpitheliumEventF-ActinFaceFailureGenesGeneticGoalsHumanImageIndividualKineticsKnowledgeLearningLifeMeasurableMechanicsMembraneMicrofilamentsModelingMorphogenesisMotor ActivityMyosin ATPaseOrganismPhasePhenotypeProcessProteinsRegulationRoleShapesSystemTestingTimeTissuesVinculinWorkbasecellular microvillusconstrictionconvergent extensioncrosslinkdepolymerizationdesignembryo cellenvironmental agentfallsgenome editinghuman diseasemembermultidisciplinarynovelpolymerizationpreventpublic health relevanceresearch study
项目摘要
DESCRIPTION (provided by applicant): Changes in cell shape drive morphogenesis and actin deficiencies cause failed cell shape change and birth defects. Yet our knowledge of actin's influence on morphogenesis is largely limited to lists of molecules and descriptions of gross phenotypes. While actin filaments (F-actin) are recognized as the major structural determinant of cell shape, basic questions remain unanswered: How is F-actin remodeled? How does it inter- face with cell membranes? How does it adapt to environmental or genetic variability? We need these answers to understand development and human disease. Our long-term goal is to fully understand actin's role in forming healthy tissues. We are focused on Drosophila cellularization, the process that builds the first epithelial sheet in the embryo. During cellularization, three cell surface remodeling events are going on in every new cell of the embryo: (i) microvilli disassemble; (ii) a membrane furrow ingresses; and (iii) an actomyosin ring contracts. We have shown that while these three remodeling events are spatially segregated over tens of microns, they are still kinetically coupled to each other and to measurable changes in the actomyosin ring. We have also identified specific F-actin regulators in the actomyosin ring that promote the robustness of cellularization against environmental and genetic perturbation. These results argue that actin does more than just give cells their shape. Our working model is that actin- based mechanisms also contribute to the coordination, kinetics, and robustness of morphogenesis. In this proposed work, we will test our model as follows: In Aim 1, we will test the hypothesis that plasma membrane tension, generated by furrow ingression, suppresses F-actin polymerization in microvilli, causing them to "unfold" or fall apart. In Aim 2, we will test he hypothesis that distinct kinetic phases of actomyosin ring contraction are governed by distinct mechanisms of F-actin regulation. In Aim 3, we will test the hypothesis that F-actin regulators, Srya and Spt, stabilize F-actin within the contractile ring to ensure robust cellularization in the
face of environmental and genetic perturbation. We have assembled a multidisciplinary team of physicists, mathematicians and technologists; and we will employ a powerful combination of approaches, including quantitative live imaging, physical force assays, genetics, and genome editing to examine the events of cellularization in uncommon detail. Because the actin- based machinery that drives cellularization is widely conserved, our findings will be relevant to other organ- isms, including humans. We will establish how individual remodeling events are regulated in space and time, while also showing how the events are coordinated with each other to accomplish cellularization at high fidelity. In doing this work, we will also reveal how genes, mechanics, and environment regulate F-actin.
描述(由申请人提供):细胞形状的变化驱动形态发生,肌动蛋白缺陷导致细胞形状改变失败和出生缺陷,然而我们对肌动蛋白对形态发生的影响的了解很大程度上局限于分子列表和总体表型的描述。 F-肌动蛋白)被认为是细胞形状的主要结构决定因素,但基本问题仍未得到解答:F-肌动蛋白如何重塑?它是否适应环境或遗传变异?我们需要这些答案来了解发育和人类疾病。我们的长期目标是充分了解肌动蛋白在形成健康组织中的作用,即果蝇细胞化,即构建第一个上皮细胞的过程。在细胞化过程中,胚胎的每个新细胞都会发生三个细胞表面重塑事件:(i) 微绒毛分解;(ii) 膜沟进入;(iii) 肌动球蛋白形成。我们已经证明,虽然这三个重塑事件在空间上隔离了数十微米,但它们仍然在动力学上相互耦合,并且与肌动球蛋白环中可测量的变化相关。这些结果表明,肌动蛋白不仅仅赋予细胞形状,而且基于肌动蛋白的机制还有助于协调,在这项拟议的工作中,我们将按如下方式测试我们的模型:在目标 1 中,我们将测试由沟进入产生的膜等离子体张力抑制微绒毛中的 F-肌动蛋白聚合,从而导致它们聚合的假设。在目标 2 中,我们将测试肌动球蛋白环收缩的不同动力学阶段受 F-肌动蛋白调节的不同机制控制的假设。假设 F-肌动蛋白调节因子 Sria 和 Spt 将 F-肌动蛋白稳定在收缩环内,以确保细胞内稳健的细胞化
面对环境和遗传扰动,我们组建了一支由物理学家、数学家和技术人员组成的多学科团队,我们将采用强大的方法组合,包括定量实时成像、物理力测定、遗传学和基因组编辑来研究细胞化事件。由于驱动细胞化的基于肌动蛋白的机制广泛保守,因此我们的发现将与包括人类在内的其他生物体相关,我们将确定个体重塑事件如何在空间和时间上受到调节。展示这些事件如何相互协调以实现高保真度的细胞化。在这项工作中,我们还将揭示基因、机制和环境如何调节 F-肌动蛋白。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ANNA M SOKAC', 18)}}的其他基金
Beyond cell shape: Actin exerts systems-level control during morphogenesis
超越细胞形状:肌动蛋白在形态发生过程中发挥系统级控制
- 批准号:
9303413 - 财政年份:2015
- 资助金额:
$ 30.51万 - 项目类别:
Beyond cell shape: Actin exerts systems-level control during morphogenesis
超越细胞形状:肌动蛋白在形态发生过程中发挥系统级控制
- 批准号:
9099863 - 财政年份:2015
- 资助金额:
$ 30.51万 - 项目类别:
F-Actin Remodeling at Newly Forming Cell-Cell Junctions
新形成的细胞-细胞连接处的 F-肌动蛋白重塑
- 批准号:
6930423 - 财政年份:2004
- 资助金额:
$ 30.51万 - 项目类别:
F-Actin Remodeling at Newly Forming Cell-Cell Junctions
新形成的细胞-细胞连接处的 F-肌动蛋白重塑
- 批准号:
6836413 - 财政年份:2004
- 资助金额:
$ 30.51万 - 项目类别:
F-Actin Remodeling at Newly Forming Cell-Cell Junctions
新形成的细胞-细胞连接处的 F-肌动蛋白重塑
- 批准号:
7117319 - 财政年份:2004
- 资助金额:
$ 30.51万 - 项目类别:
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