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Transcriptional control of collective cell migration

集体细胞迁移的转录控制

基本信息

批准号：
9344648
负责人：
Lionel Christiaen
金额：
$ 31.96万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-23 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9344648
关键词：
Actins Adhesions Alpha Cell Animals Attention Automobile Driving Basal lamina Behavior Biological Assay CRISPR/Cas technology Cardiac Cell Polarity Cell membrane Cell physiology Cell-Matrix Junction Cells Chordata Ciona intestinalis Collagen Competence Complement Computer Simulation Development Embryo Embryonic Development Endocytosis Endoderm Endosomes Epidermis Extracellular Matrix Fibroblast Growth Factor Future Gene Expression Genes Genetic Transcription Germ Layers Goals Integrins Invertebrates Libraries Link MAP Kinase Gene Maintenance Maps Mediating Mesoderm Cell Modeling Monitor Neoplasm Metastasis Output Pathologic Pathologic Processes Pattern Phenotype Physiological Physiological Processes Positioning Attribute Process Property Receptor Protein-Tyrosine Kinases Receptor Signaling Recycling Regenerative Medicine Regulation Regulator Genes Research Role Side Signal Transduction Structure System Talin Testing Tissues Transcriptional Regulation Urochordata Vascular Endothelial Growth Factors Vertebrates Vesicle Wound Healing ascidian blood vessel development cancer prevention cell behavior cell motility discoidin domain receptor 2 discoidin receptor imaging modality insight interest loss of function metastasis prevention migration novel polarized cell progenitor quantitative imaging receptor receptor expression receptor function receptor upregulation rho GTP-Binding Proteins trafficking transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Critical physiological and pathological processes, such as wound healing, blood vessel formation and cancer metastasis, rely on directed collective cell migrations, whereby groups of cells collectively polarize and move together in an orderly fashion. The ability of cell collectives to migrate directionally is determined in part by the tissue-specific transcriptional inputs that define the complement of expressed genes and thus their competence to migrate. The long-term goal of this project is to understand how tissue-specific transcription regulators control the basic cellular processes underlying directed collective cell migration. To this aim, the simplified embryos of a chordate species, the ascidian Ciona intestinalis, will be used to study the migration of pre- cardiac mesoderm cells, called “trunk ventral cells” (TVCs). The TVCs provide the simplest possible model of directed collective cell migration in live embryos. On each side of the embryo, only two cells migrate together and display a clear Leader-Trailer polarity aligned with the direction of migration: the leader TVC displays a broad leading edge and more conspicuous protrusions than the trailer. It was previously established that Mesp, Fibroblast growth factor (Fgf) signaling and FoxF transcriptional inputs determine the ability of TVCs to migrate. Moreover, TVCs migrate strictly between the endodermal and ectodermal germ layers, a hallmark of mesodermal cardiac progenitors. It was determine that these surrounding tissues contribute to canalizing TVCs' innate motility towards collective polarity and directed migration. The goal of the proposed research is to understand how transcriptionally-controlled intrinsic TVC properties interface with extrinsic signals to determine collective polarity and directed migration in the embryo. Preliminary studies suggested that the gene encoding the discoidin domain receptor (Ddr) is upregulated by Mesp, FGF and FoxF transcriptional inputs in the TVCs, where it promotes adhesion to the epidermis. Using newly developed quantitative imaging methods, the detailed mechanisms controlling Ddr expression, localization and activity will be analyzed. The hypothesis that a cell-autonomous antagonism between Ddr and vascular endothelial growth factor receptor (Vegfr) signaling positions the migrating TVCs between the epidermis and endoderm will be tested. Preliminary observations suggest that Ddr promotes adhesion to the epidermis by regulating vesicle trafficking. The hypothesis that Ddr acts in Rab4/Rab11-positive endosomes to promote the recycling of integrins to the plasma membrane will be tested. Finally, the functions of regulated candidate effectors of collective migration will be studied extensively using TVC-specific CRISPR/Cas9-mediated loss-of-function assays and high-content phenotypic analyses. A provisional model of the biomolecular network controlling the subcellular processes underlying TVC behavior will be built. Particular attention will be paid to the candidate modulators of Ddr, Vegfr and integrin functions. Completion of this project will illuminate the systems' level mechanisms linking intrinsic transcriptional inputs and extrinsic signals to define cell-specific behaviors.

项目摘要/摘要