Investigating mechanisms regulating cytoskeletal dynamics and alignment during epithelial tissue folding
研究上皮组织折叠过程中细胞骨架动力学和排列的调节机制
基本信息
- 批准号:10598503
- 负责人:
- 金额:$ 7.18万
- 依托单位:
- 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:2021-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActomyosinAdherens JunctionAdultAffectApicalApoptosisAutomobile DrivingBehaviorCancer BiologyCell ShapeCellsCellular biologyChemicalsCollectionCongenital AbnormalityConnective TissueCytoskeletal ModelingCytoskeletonDedicationsDefectDeformityDevelopmentDevelopmental BiologyDiseaseDisease ProgressionDisputesDrosophila genusDrosophila melanogasterEmbryoEmbryonic DevelopmentEpitheliumEventF-ActinFailureFogsGene ExpressionGeneticGoalsHealthHumanImageImage AnalysisIndividualIntercellular JunctionsKnowledgeLabelLightLinkMalignant NeoplasmsMeasuresMechanicsMesenchymalMesodermMethodsMicrofilamentsMicroscopyMissionMolecularMolecular MotorsMorphogenesisMotorMovementMyosin ATPaseMyosin S-2Myosin Type IINatureNeoplasm MetastasisNeural Tube DefectsNeural tubeOrganOutcomePhysiologic pulseProcessProductionResearchRoleSeminalShapesSignal PathwaySignal TransductionStructureSurfaceTWIST1 geneTestingTissuesUnited States National Institutes of HealthWorkalpha cateninbehavior predictioncomparativeconstrictioncrosslinkdevelopmental diseasedriving forceepithelial to mesenchymal transitiongastrulationimaging modalityinnovationinsightintercellular connectionmechanical forcemechanical signalmutantmyosin phosphatasenon-muscle myosinnovelphysical propertypredictive modelingpreventquantitative imagingsingle moleculesuperresolution imagingsuperresolution microscopytraining opportunitytransmission processtumor progression
项目摘要
Project Summary:
Large-scale tissue movements are critical during development to transform an amorphous collection of
cells into organs with specific structure and function. Abnormal activation of force-generating signals that
regulate epithelial morphogenesis can result in developmental defects, such as neural tube deformities, as well
as aberrant epithelial-mesenchymal transition and cancer metastasis. Yet we do not fully understand how
mechanical forces generated at the molecular level regulate epithelial remodeling. At the cellular level, most
forces are generated by the actomyosin network; the molecular motor non-muscle myosin II (myosin)
crosslinks actin filaments (F-actin), thereby generating contractile forces which are propagated throughout the
tissue via intercellular connections. One outcome of actomyosin contractility is apical contraction, in which the
apex of the cell narrows as a result of repeated bursts of myosin pulses that condense the F-actin cortex in a
ratchet-like manner. When myosin pulsing and ratcheting is disrupted, cells fail to apically constrict and the
tissue fails to fold. However, the mechanisms driving pulsatile contractions and ratcheting behavior remains
poorly understood, highlighting a critical gap in our understanding of how upstream signaling events are
intricately linked to downstream changes in cytoskeletal organization and behavior. The long-term goal of this
project is to determine how mechanical forces generated at the molecular level collectively drive tissue-wide
morphogenetic changes. The overall objective of this proposal is to identify mechanisms that regulate myosin
dynamics and alignment by determining the mechanistic link between Twist expression and myosin turnover.
The rationale for this proposed work is to gain insight not only into the nature of these mechanisms, but also
the general principles governing contractility and ratchet-like apical constriction during large-scale tissue
movements. Our central hypothesis is that Twist, and its downstream effectors, as well as tissue-wide forces,
via intercellular connections, cooperatively regulate myosin dynamics to drive apical ratcheting and tissue
remodeling events during embryonic development in Drosophila. This hypothesis will be tested by pursuing two
specific aims: we will (1) determine the mechanism through which Twist promotes cell apex stabilization, and
(2) determine how myosin dynamics are affected by intercellular connectivity. Our approach is innovative
because it is one of the first to directly examine myosin dynamics using an integrative strategy that combines
classic Drosophila genetics with advanced microscopy methods, including photo-conversion and super-
resolution imaging. The proposed research is significant because it will advance our understanding of the
connection between gene expression, signaling pathways, and force production during epithelial
morphogenesis, and will provide new perspective to ongoing research efforts investigating developmental
diseases and cancer biology.
项目概要:
大规模的组织运动在发育过程中是至关重要的,
将细胞转化为具有特定结构和功能的器官。力产生信号的异常激活,
调节上皮形态发生也会导致发育缺陷,如神经管畸形,
异常上皮间质转化和癌症转移。但我们并不完全理解
在分子水平上产生的机械力调节上皮重塑。在细胞水平上,大多数
力由肌动球蛋白网络产生;分子马达非肌肉肌球蛋白II(肌球蛋白)
交联肌动蛋白丝(F-肌动蛋白),从而产生的收缩力,这是整个传播
组织通过细胞间的连接。肌动球蛋白收缩性的一个结果是心尖收缩,其中
由于肌球蛋白脉冲的重复爆发,细胞的顶端变窄,肌球蛋白脉冲将F-肌动蛋白皮层浓缩成一个小的细胞,
棘轮般的方式。当肌球蛋白脉冲和棘轮作用被破坏时,细胞不能进行顶端收缩,
组织不能折叠。然而,驱动脉动收缩和棘轮行为的机制仍然存在,
我们对此知之甚少,这突出了我们对上游信号事件如何影响人类的理解方面的一个关键空白。
与细胞骨架组织和行为的下游变化密切相关。长期目标是
一个项目是确定在分子水平上产生的机械力如何共同驱动组织范围内的
形态发生变化这项建议的总体目标是确定调节肌球蛋白的机制
通过确定Twist表达和肌球蛋白周转之间的机械联系来确定动力学和对齐。
这项拟议工作的基本原理是不仅要深入了解这些机制的性质,
在大规模组织的收缩性和棘齿状顶端收缩的一般原则
动作我们的中心假设是,扭曲,及其下游效应器,以及组织范围的力量,
通过细胞间连接,协同调节肌球蛋白动力学,以驱动顶端棘轮和组织
果蝇胚胎发育过程中的重塑事件。这一假设将通过两个
具体目标:我们将(1)确定Twist促进细胞顶端稳定的机制,
(2)确定肌球蛋白动力学如何受到细胞间连接的影响。我们的方法是创新的
因为它是第一个直接研究肌球蛋白动力学的方法,
经典的果蝇遗传学与先进的显微镜方法,包括光转换和超级,
分辨率成像这项拟议中的研究意义重大,因为它将促进我们对
上皮细胞生长过程中基因表达、信号通路和力产生之间的联系
形态发生,并将提供新的视角,正在进行的研究工作,调查发展
疾病和癌症生物学。
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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Mary Ann Collins其他文献
The dynamics and biophysics of shape formation: Common themes in plant and animal morphogenesis
形态形成的动力学和生物物理学:植物和动物形态发生的共同主题
- DOI:
10.1016/j.devcel.2023.11.003 - 发表时间:
2023-12-18 - 期刊:
- 影响因子:8.700
- 作者:
Isabella Burda;Adam C. Martin;Adrienne H.K. Roeder;Mary Ann Collins - 通讯作者:
Mary Ann Collins
Mary Ann Collins的其他文献
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{{ truncateString('Mary Ann Collins', 18)}}的其他基金
Investigating mechanisms regulating cytoskeletal dynamics and alignment during epithelial tissue folding
研究上皮组织折叠过程中细胞骨架动力学和排列的调节机制
- 批准号:
10396453 - 财政年份:2021
- 资助金额:
$ 7.18万 - 项目类别:
Investigating mechanisms regulating cytoskeletal dynamics and alignment during epithelial tissue folding
研究上皮组织折叠过程中细胞骨架动力学和排列的调节机制
- 批准号:
10229158 - 财政年份:2021
- 资助金额:
$ 7.18万 - 项目类别:
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