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Regulation of mediolateral cell polarity by PCP and notochord boundary signaling

PCP 和脊索边界信号传导调节内侧细胞极性

基本信息

批准号：
9055556
负责人：
Margot L.K. Williams
金额：
$ 5.61万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9055556
关键词：
4D Imaging Alleles Animals Anterior Cell Polarity Cells Cessation of life Chromatin Complex Craniorachischises Cre-LoxP Cues Data Defect Deposition Development Embryo Embryonic Development Enhancers Exhibits Extracellular Matrix Failure Fetus Fishes Future Gastrula Gene Expression Genes Head Intercalated Cell Life Ligands Mediating Mesoderm Mesoderm Cell Modeling Molecular Molecular Profiling Morphogenesis Mutation Nature Neural Tube Closure Paraxial Mesoderm Pathway interactions Pattern Phenotype Population Process Regulation Reporting Role Signal Transduction Somites Spinal Dysraphism System Tail Testing Time Transgenic Organisms Transplantation Zebrafish base cell behavior cell motility cell type disability embryo tissue gastrulation intercalation mutant notochord novel overexpression planar cell polarity polarized cell public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): All animal embryos, which begin as a disc or sphere, form an elongated body axis with a head on one end and a tail on the other. This fundamental process of axial elongation is accomplished by convergence and extension (C&E) of embryonic tissues, a process driven by polarized cell behaviors such as cell migration and mediolateral (ML) intercalation during gastrulation. Although molecular regulation of ML cell polarity in embryonic tissues is largely attributed to planar cell polarity (PCP) signaling, there is evidence that signals from the notochord-somite boundary (NSB) are also involved. The nature of this NSB signal and its relationship to PCP signaling are not understood. The Solnica-Krezel lab has identified the chromatin factor Ugly duckling (Udu)/Gon4l as a novel regulator of C&E in zebrafish. Maternal zygotic (MZ) udu mutant embryos display an extremely short anterior-posterior axis, and interestingly, abnormal NSB and reduced ML polarity of boundary-adjacent cells. Complete loss of udu/gon4l function enhances axis elongation defects in PCP mutant embryos, and PCP-dependent cell polarity appears to be unaffected in MZudu embryos, suggesting that udu/gon4l regulates ML cell polarity in parallel to the PCP pathway. We found that expression of slit3, which encodes a repulsive ECM ligand, is increased in MZudu embryos. Expression of Slit3 and its Robo receptors in the axial mesoderm of WT embryos predict a role for Slit-Robo signaling in formation of normal axial mesoderm and the NSB. Furthermore, overexpression of slit3 disrupts NSB formation and C&E in zebrafish embryos, and exacerbates axis elongation defects in PCP mutants. I hypothesize that udu/gon4l is required for intact Slit-Robo signaling at the NSB, which mediates a novel polarity cue that acts in parallel to PCP to regulate ML cell polarity underlying C&E. Characterization of this novel polarity cue, and its relationship to known polarity signals, will further our understanding of how complex positional and morphogenetic cues are coordinated during vertebrate embryogenesis.

描述（由申请人提供）：所有动物胚胎，开始为圆盘或球体，形成一个细长的体轴，一端是头，另一端是尾。这个轴向伸长的基本过程是通过胚胎组织的会聚和伸展（C&E）来完成的，这是由极化细胞行为驱动的过程，例如原肠胚形成期间的细胞迁移和中外侧（ML）插入。虽然胚胎组织中ML细胞极性的分子调控主要归因于平面细胞极性（PCP）信号，但有证据表明，来自脊索-体节边界（NSB）的信号也参与其中。该NSB信号的性质及其与PCP信号的关系尚不清楚。Solnica-Krezel实验室已经确定了染色质因子丑小鸭（Udu）/Gon 4l作为斑马鱼C&E的新型调节因子。母亲合子（MZ）udu突变胚胎显示一个非常短的前后轴，有趣的是，异常NSB和减少ML极性的边界相邻细胞。完全丧失udu/gon 4l功能增强PCP突变胚胎中的轴伸长缺陷，并且PCP依赖的细胞极性似乎在MZudu胚胎中不受影响，这表明udu/gon 4l调节ML细胞极性与PCP途径平行。我们发现，在MZudu胚胎中，编码排斥性ECM配体的slit 3的表达增加。Slit 3及其Robo受体在WT胚胎的轴向中胚层中的表达预测了Slit-Robo信号传导在正常轴向中胚层和NSB形成中的作用。此外，slit 3的过表达破坏了斑马鱼胚胎中的NSB形成和C&E，并加剧了PCP突变体中的轴伸长缺陷。我假设udu/gon 4l是NSB完整的Slit-Robo信号所必需的，它介导一种新的极性线索，与PCP平行作用，以调节C&E相关的ML细胞极性。表征这种新的极性线索，其与已知的极性信号的关系，将进一步我们了解复杂的位置和形态发生的线索是如何协调在脊椎动物胚胎发生。