Protrusive behavior during collective cell migration

集体细胞迁移过程中的突出行为

基本信息

批准号：
10595559
负责人：
Alex Nechiporuk
金额：
$ 30.8万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595559
关键词：
Abnormal Cell Actins Acute Address Adult Affect Behavior Biological Models Blood Vessels Cadherins Cell Differentiation process Cells Complex Congenital Abnormality Cues Defect Development Disease Embryo Embryonic Development Environment Epithelial Cells Epithelium F-Actin Fluorescence Resonance Energy Transfer Foundations Future Gene Expression Genes Genetic Transcription Health Image In Situ Hybridization Individual Invaded Label Malignant Neoplasms Mediating Modeling Molecular Molecular Target Morphogenesis Movement Mutation Neural Crest Cell Neural Tube Closure Pattern Play Primordium Process Proteins Role Shapes Signal Pathway Signal Transduction Specimen Structure Testing Tissues Tumor Cell Invasion WNT Signaling Pathway Zebrafish cell motility combat developmental disease differential expression extracellular gain of function genetic approach individual response inhibitor insight lateral line loss of function mRNA Differential Displays mechanical force migration mosaic mosaic analysis mutant neoplastic cell novel organ growth premature sensor transcriptome sequencing transmission process wound healing

Abnormal Cell Actins Acute Address Adult Affect Behavior Biological Models Blood Vessels Cadherins Cell Differentiation process Cells Complex Congenital Abnormality Cues Defect Development Disease Embryo Embryonic Development Environment Epithelial Cells Epithelium F-Actin Fluorescence Resonance Energy Transfer Foundations Future Gene Expression Genes Genetic Transcription Health Image In Situ Hybridization Individual Invaded Label Malignant Neoplasms Mediating Modeling Molecular Molecular Target Morphogenesis Movement Mutation Neural Crest Cell Neural Tube Closure Pattern Play Primordium Process Proteins Role Shapes Signal Pathway Signal Transduction Specimen Structure Testing Tissues Tumor Cell Invasion WNT Signaling Pathway Zebrafish cell motility combat developmental disease differential expression extracellular gain of function genetic approach individual response inhibitor insight lateral line loss of function mRNA Differential Displays mechanical force migration mosaic mosaic analysis mutant neoplastic cell novel organ growth premature sensor transcriptome sequencing transmission process wound healing

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项目摘要

Cell migration is one of the fundamental processes shaping the developing embryo. Collective cell migration is a specialized form of coordinated cellular migration where cells maintain cell-cell contacts, group polarization, and coordinated behavior. Collective cell migration is essential for numerous processes during development, including neural tube closure, blood vessel branching, and neural crest cell migration. Consequently, disruption of this process during development can lead to severe birth defects. There is also a growing body of evidence that epithelial tumor cells move as cohesive groups during tissue invasion, in a process termed collective cell invasion, which is analogous to collective cell migration during embryogenesis. Thus, a mechanistic understanding of collective cell migration should provide important new insights into tissue morphogenesis during embryogenesis and abnormal cell migration in diseases. However, the molecular mechanisms that regulate collective cell migration remain poorly defined. As cells migrate, they must extend protrusions to interact with the extracellular environment, sense chemotactic cues, and act as points of attachments and signaling centers to coordinate the migratory behavior. The regulators of protrusive behavior have been widely studied in cells that migrate individually; however, how protrusive behavior is controlled throughout collectives is not well understood. To tackle this problem, we are using unique advantages of the zebrafish model system, including amenity to live imaging and advanced genetic approaches. Using mosaic labeling of filamentous actin, we discovered an abundance of brush-like, actin-based protrusions in multiple cells across the migrating collective. Live imaging revealed that these previously undescribed structures are highly dynamic, oriented towards the direction of migration, and prevalent in the leading part of the collective. We further demonstrated that these protrusions are Arp2/3 dependent and are required for collective cell migration. We have previously shown that the canonical Wnt signaling is necessary for cell movement during collective cell migration. We have also found that a high number of Wnt target genes are known regulators of actin dynamics; these genes are expressed in distinct regions of the collective and their expression pattern is perturbed under Wnt-deficient conditions. We therefore hypothesize that protrusive behavior during collective cell migration is coordinated by a differential activity of Wnt target genes that regulate actin dynamics. To test this hypothesis, we will 1) define the type of protrusions and molecular machinery that regulates their activity; 2) determine the role of major signaling pathways, including Wnt and Fgf, in regulating this behavior; and 3) identify novel regulators of protrusive behavior during collective cell migration. Better understanding of collective cell migration during organ development will help to elucidate how this process is disrupted in various developmental disorders as well as during cancer invasion.

细胞迁移是塑造发育中胚胎的基本过程之一。集体细胞迁移是一种专门形式的协调性细胞迁移，其中细胞维持细胞 - 细胞接触，组极化，和协调的行为。集体细胞迁移对于开发过程中的许多过程至关重要，包括神经管闭合，血管分支和神经rest细胞迁移。因此，破坏了在开发过程中的这一过程可能会导致严重的先天缺陷。也越来越多的证据在组织入侵期间，该上皮肿瘤细胞在被称为集体细胞的过程中作为凝聚组移动侵袭，类似于胚胎发生过程中的集体细胞迁移。因此，一种机械对集体细胞迁移的理解应为组织形态发生提供重要的新见解在疾病中的胚胎发生和异常细胞迁移过程中。但是，分子机制规范的集体细胞迁移仍然很差。当细胞迁移时，它们必须将突出扩展到与细胞外环境相互作用，感官趋化线索，并充当依恋点和信令中心以协调迁移行为。突出行为的调节因子已广泛在单独迁移的细胞中进行了研究；但是，如何在整个集体中控制突出行为不太了解。为了解决这个问题，我们使用斑马鱼模型系统的独特优势，包括实时成像和先进遗传方法的便利。使用丝状的镶嵌标记肌动蛋白，我们在迁移的多个细胞中发现了多种类似刷子的基于肌动蛋白的突起集体。实时成像表明，这些以前未描述的结构是高度动态的，取向的朝向迁移的方向，并在集体的主要部分中盛行。我们进一步证明了这些突起是ARP2/3依赖性的，是集体细胞迁移所必需的。我们以前有表明在集体细胞迁移过程中，规范Wnt信号对于细胞运动是必需的。我们还发现，大量的Wnt靶基因是肌动蛋白动力学的已知调节剂。这些基因在集体的不同区域中表达，其表达模式在Wnt缺乏症状下受到干扰状况。因此，我们假设集体细胞迁移期间的凸出行为由 Wnt靶基因调节肌动蛋白动力学的差异活性。为了检验这一假设，我们将1）定义调节其活性的突起和分子机制的类型； 2）确定在调节这种行为时，包括Wnt和FGF在内的主要信号通路； 3）确定新颖的调节剂集体细胞迁移期间的突出行为。更好地了解集体细胞迁移器官开发将有助于阐明如何在各种发育障碍中破坏这一过程以及在癌症入侵期间。