Inductive and morphogenetic processes shaping the zebrafish embryonic axes

塑造斑马鱼胚胎轴的诱导和形态发生过程

基本信息

批准号：
9918423
负责人：
LILIANNA SOLNICAKREZEL
金额：
$ 63.29万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918423
关键词：
Adhesions Anterior Behavior Cadherins Calcium Signaling Cell Polarity Cell membrane Cells Complex Congenital Abnormality Cytoskeleton Development Diagnosis Disease Dorsal Embryo Embryonic Development Ensure Fatty acid glycerol esters G-Protein-Coupled Receptors Genes Germ Layers Individual Link Membrane Mesenchymal Microtubules Morphogenesis Movement Mutation Pathway interactions Pattern Phenotype Phosphotransferases Process Proteins Research Role Shapes Signal Transduction Spontaneous abortion System Testing Time Vertebrates Work Zebrafish beta catenin chemokine driving behavior gastrulation interest loss of function mutant planar cell polarity polarized cell public health relevance therapy development zygote

Adhesions Anterior Behavior Cadherins Calcium Signaling Cell Polarity Cell membrane Cells Complex Congenital Abnormality Cytoskeleton Development Diagnosis Disease Dorsal Embryo Embryonic Development Ensure Fatty acid glycerol esters G-Protein-Coupled Receptors Genes Germ Layers Individual Link Membrane Mesenchymal Microtubules Morphogenesis Movement Mutation Pathway interactions Pattern Phenotype Phosphotransferases Process Proteins Research Role Shapes Signal Transduction Spontaneous abortion System Testing Time Vertebrates Work Zebrafish beta catenin chemokine driving behavior gastrulation interest loss of function mutant planar cell polarity polarized cell public health relevance therapy development zygote

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项目摘要

DESCRIPTION (provided by applicant): How does a vertebrate animal body develop from a single cell is an overarching question of my research. Despite much progress, many basic mechanisms underlying embryogenesis remain poorly understood. I am particularly interested how the inductive and morphogenetic processes that establish the embryonic body plan are coordinated in space and time to ensure normal development. Specification of anteroposterior and dorsoventral embryonic axis in the zebrafish zygote involves microtubule dependent transport of factors promoting dorsal Wnt/β-catenin activity, which patterns germ layers and coordinates gastrulation movements. We showed that Ccl19.1 chemokine signaling through Ccr7 G protein-coupled receptor (GPCR) limits axis formation by downregulating β-catenin. Using mutations in ccl19.1 and ccr7 zebrafish genes we will delineate the pathways through which they regulate calcium signaling and limit axis formation. We recently discovered that Dachsous (Dchs) cadherins regulate cytoskeleton in the zygote and during axis formation. Whereas Dchs is commonly known to interact with Fat cadherin and Fjx1 kinase, we will characterize Fat/Fjx1-dependent and independent roles of Dchs. We will identify proteins interacting with Dchs to define its functional links to cytoskeleton and other effectors. During gastrulation, convergence and extension (C&E) movements elongate the germ layers anteroposteriorly and narrow them dorsoventrally. Wnt/Planar Cell Polarity (Wnt/PCP) signaling is a conserved regulator of polarized cell behaviors driving C&E in vertebrates. Our studies posit that Wnt/PCP signaling works during gastrulation as a cellular compass coordinating polarity and behaviors of individual cells with anteroposterior embryonic polarity, in part by asymmetric distribution of PCP components at anterior and posterior cell membranes. To understand how the planar asymmetries of PCP components arise in dynamic mesenchymal cells, we will test the hypothesis that adhesion GPCR, Gpr125, a new PCP component, promotes formation of the posteriorly enriched membrane PCP complexes. We will determine whether Dchs works with Fat and Fjx1 during gastrulation to polarize microtubules and regulate Wnt/PCP signaling-dependent cell polarity. Finally, we will test whether the Dchs/Fat/Fjx1 system provides a mechanism to link Wnt/PCP signaling to global embryo patterning. To uncover additional chemokine GPCRs involved in axis formation and gastrulation, we will interrogate functions of the subset of 21 chemokine GPCRs expressed during embryogenesis by characterizing loss-of-function single and compound mutant phenotypes. As mutations in the components of the Wnt, Dchs/Fat and GPCR pathways cause miscarriages, birth defects and diseases; our studies can advance their understanding, diagnosis and facilitate development of therapies.

描述（由适用提供）：单个细胞中脊椎动物动物体的发育如何是我研究的总体问题。尽管取得了很多进展，但胚胎发生的许多基本机制仍然很少了解。我特别感兴趣的是建立胚胎身体计划的诱导和形态发生过程如何在时空协调以确保正常发育。斑马鱼合子中前后和背腹胚胎轴的规格涉及促进背wnt/β-catenin活性因子的微管依赖性运输，该因素会模拟胚芽层，并坐标过层。我们表明，CCL19.1通过CCR7 G蛋白偶联受体（GPCR）的趋化因子信号传导通过下调β-catenin来形成轴。使用CCL19.1和CCR7斑马鱼基因中的突变，我们将描述它们调节钙信号传导和限制轴形成的途径。我们最近发现，碳硫蛋白（DCHS）钙粘蛋白调节合子中和轴形成期间的细胞骨架。尽管DCHS通常与脂肪钙粘着蛋白和FJX1激酶相互作用，但我们将表征DCH的脂肪/FJX1依赖性和独立的作用。我们将确定与DCH相互作用的蛋白质，以定义其与细胞骨架和其他作用的功能联系。在口腔化期间，收敛和延伸（C＆E）运动拉长了细菌层前后延伸，并且背侧缩小它们。 Wnt/Planar细胞极性（WNT/PCP）信号传导是驱动脊椎动物C＆E的极化细胞行为的保守调节剂。我们的研究政策是，Wnt/PCP信号在过度时起作用，作为细胞指南针，将单个细胞与前后胚胎前极性的极性和行为进行协调，部分原因是在前和后细胞机制下PCP成分的不对称分布。为了了解PCP成分的平面不对称是如何在动态间充质细胞中产生的，我们将测试以下假设：粘合剂GPCR，GPR125（一种新的PCP组件）促进了后部富集的膜PCP复合物的形成。我们将确定DCHS在过度化微管偏振和调节Wnt/PCP信号依赖性细胞极性时是否与脂肪和FJX1一起使用。最后，我们将测试DCHS/FAT/FJX1系统是否提供了将Wnt/PCP信号与全局胚胎图案联系起来的机制。为了揭示参与轴形成和口腔化的其他趋化因子GPCR，我们将通过表征功能丧失的单一和复合突变体表型来审问在胚胎发生过程中21个趋化因子GPCR子集的功能。作为Wnt，DCHS/FAT和GPCR途径的组件中的突变会导致流产，出生缺陷和疾病；我们的研究可以提高他们的理解，诊断并促进疗法的发展。