INBRE: KU-L: TAIL MORPHOGENESIS IN ZEBRAFISH

INBRE：KU-L：斑马鱼的尾部形态发生

• 批准号: 7610222
• 负责人: CHRISTOPHER J THORPE
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610222
• 关键词: Adherens Junction; Adhesions; Affect; Cells; Commit; Computer Retrieval of Information on Scientific Projects Database; Decision Making; Defect; Development; Embryo; Ensure; Funding; Genes; Genetic screening method; Goals; Grant; Human; Imaging Techniques; Institution; Label; Location; Morphogenesis; Multipotent Stem Cells; Neoplasm Metastasis; Organism; Pathway interactions; Pattern; Phenotype; Plastics; Population; Process; Proteins; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Stem cells; Tail; Testing; Tissues; Undifferentiated; United States National Institutes of Health; Zebrafish; base; blastomere structure; cell motility; in vivo; insight; rho GTPase-activating protein; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In order to generate a properly patterned organism, embryonic cells must integrate multiple signaling inputs that govern proliferation, differentiation, polarity, and motility. Many critical factors that regulate patterning of cells or tissues during development promote tumorigenesis and metastasis when misregulated postembryonically. Understanding how cells make decisions about when and where to migrate, and whether to differentiate or remain plastic, is the main goal of our project, and will provide insight into the general mechanisms coordinating cell fate and motility during development and oncogenesis. During vertebrate development, tissues of the posterior body are derived from a population of multipotent progenitor cells called the tailbud. Fate specification, differentiation, and cell migration are carefully coordinated within the tailbud to ensure that, as some cells exit the tailbud and become committed to specific fates, other cells are retained in the tailbud as undifferentiated precursors to support later tail outgrowth. Very little is known about how these processes are coordinated, however. We have found that misregulation of a Rho GTPase Activating Protein (GAP) called ARHGAP10, in conjuction with components of a noncanonical Wnt pathway that regulates cell movements in the embryo, causes pluripotent tailbud cells to mislocalize and direct the formation of a secondary tail. Loss of BMP activity has previously been shown to result in a similar phenotype, suggesting that multiple signaling inputs are required to restrict multipotent tailbud cells to only their appropriate location in the embryo. To begin an analysis of this process, we will: 1) Test genetic interactions between previously identified components to gain insight into how these signaling inputs are coordinated; we will assess the potential role of additional genes that also regulate cell migration; 2) Test the hypothesis that ARHGAP10 functions through regulation of a RhoGTPase, specifically RhoA or Cdc42 by determining if modulating the activity of either protein affects this process; and 3) Use in vivo cell labeling and imaging techniques to determine the cellular basis of the defect-which cells are involved, and how do they get to their ectopic location, and then to test the hypothesis, suggested by studies of human ARHGAP10, that zebrafish ARHGAP10 promotes adhesion among tailbud cells by regulating the assembly or function of adherens junctions.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 为了产生一个正确的模式化生物体，胚胎细胞必须整合多种信号输入，控制增殖，分化，极性和运动性。在发育过程中调节细胞或组织模式的许多关键因子在胚后被错误调节时促进肿瘤发生和转移。了解细胞如何决定何时和何地迁移，以及是否 分化或保持可塑性，是我们项目的主要目标，并将提供深入了解在发育和肿瘤发生过程中协调细胞命运和运动的一般机制。 在脊椎动物发育过程中，后躯体的组织来源于一群多能祖细胞，称为尾芽。命运特化、分化和细胞迁移在尾芽内仔细协调，以确保当一些细胞离开尾芽并成为特定的细胞时， 在最终的结局中，其他细胞作为未分化的前体保留在尾芽中，以支持以后的尾部生长。 然而，人们对这些过程是如何协调的知之甚少。 我们已经发现，一种称为ARHGAP 10的Rho GT3激活蛋白（GAP）的错误调节，与调节胚胎细胞运动的非经典Wnt通路的组分结合，导致多能尾芽细胞错误定位并指导二级尾的形成。BMP活性的丧失以前已被证明会导致类似的表型，这表明需要多种信号输入来将多能尾芽细胞限制在胚胎中的适当位置。 为了开始对这一过程的分析，我们将：1）测试先前鉴定的组分之间的遗传相互作用，以深入了解这些信号输入是如何协调的;我们将评估也调节细胞迁移的其他基因的潜在作用; 2）测试ARHGAP 10功能的假设。 通过确定调节任一蛋白质的活性是否影响RhoGT α，特别是RhoA或Cdc 42的调节这一过程;和3）使用体内细胞标记和成像技术来确定缺陷的细胞基础-涉及哪些细胞，以及它们如何到达它们的异位位置，然后测试人类ARHGAP 10研究所提出的假设，斑马鱼ARHGAP 10通过调节粘附连接的组装或功能来促进尾芽细胞之间的粘附。