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）：所有动物胚胎都以圆盘或球体开始，形成细长的身体轴，一端有头，另一端有尾巴。轴向伸长的这一基本过程是通过胚胎组织的会聚和延伸（C&E）来完成的，该过程由极化细胞行为驱动，例如原肠胚形成期间的细胞迁移和中外侧（ML）嵌入。尽管胚胎组织中 ML 细胞极性的分子调节很大程度上归因于平面细胞极性 (PCP) 信号传导，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 信令的关系尚不清楚。 Solnica-Krezel 实验室已确定染色质因子丑小鸭 (Udu)/Gon4l 是斑马鱼 C&E 的新型调节因子。母本合子 (MZ) udu 突变胚胎表现出极短的前后轴，有趣的是，边界相邻细胞的 NSB 异常和 ML 极性降低。 udu/gon4l 功能的完全丧失会增强 PCP 突变体胚胎中的轴伸长缺陷，并且 PCP 依赖性细胞极性在 MZudu 胚胎中似乎不受影响，这表明 udu/gon4l 与 PCP 途径平行调节 ML 细胞极性。我们发现，编码排斥性 ECM 配体的lit3 的表达在 MZudu 胚胎中增加。 Slit3 及其 Robo 受体在 WT 胚胎中轴中胚层中的表达预示着 Slit-Robo 信号在正常中轴中胚层和 NSB 形成中的作用。此外，slit3 的过度表达会破坏斑马鱼胚胎中 NSB 的形成和 C&E，并加剧 PCP 突变体中的轴伸长缺陷。我假设 udu/gon4l 是 NSB 完整 Slit-Robo 信号传导所必需的，它介导一种新颖的极性线索，与 PCP 并行作用，调节 C&E 下的 ML 细胞极性。这种新颖的极性线索的表征及其与已知极性信号的关系将进一步我们对脊椎动物胚胎发生过程中复杂的位置和形态发生线索如何协调的理解。