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: 10598503
• 负责人: Mary Ann Collins
• 金额: $ 7.18万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10598503
• 关键词: Actomyosin; Adherens Junction; Adult; Affect; Apical; Apoptosis; Automobile Driving; Behavior; Cancer Biology; Cell Shape; Cells; Cellular biology; Chemicals; Collection; Congenital Abnormality; Connective Tissue; Cytoskeletal Modeling; Cytoskeleton; Dedications; Defect; Deformity; Development; Developmental Biology; Disease; Disease Progression; Disputes; Drosophila genus; Drosophila melanogaster; Embryo; Embryonic Development; Epithelium; Event; F-Actin; Failure; Fogs; Gene Expression; Genetic; Goals; Health; Human; Image; Image Analysis; Individual; Intercellular Junctions; Knowledge; Label; Light; Link; Malignant Neoplasms; Measures; Mechanics; Mesenchymal; Mesoderm; Methods; Microfilaments; Microscopy; Mission; Molecular; Molecular Motors; Morphogenesis; Motor; Movement; Myosin ATPase; Myosin S-2; Myosin Type II; Nature; Neoplasm Metastasis; Neural Tube Defects; Neural tube; Organ; Outcome; Physiologic pulse; Process; Production; Research; Role; Seminal; Shapes; Signal Pathway; Signal Transduction; Structure; Surface; TWIST1 gene; Testing; Tissues; United States National Institutes of Health; Work; alpha catenin; behavior prediction; comparative; constriction; crosslink; developmental disease; driving force; epithelial to mesenchymal transition; gastrulation; imaging modality; innovation; insight; intercellular connection; mechanical force; mechanical signal; mutant; myosin phosphatase; non-muscle myosin; novel; physical property; predictive modeling; prevent; quantitative imaging; single molecule; superresolution imaging; superresolution microscopy; training opportunity; transmission process; tumor progression

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.

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