Wnt signaling pathway interactions in early anterior-posterior neuroectoderm patterning

Wnt信号通路在早期前后神经外胚层模式中的相互作用

• 批准号: 9143401
• 负责人: Ryan Christopher Range
• 金额: $ 23.19万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2018-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143401
• 关键词: ATF2 gene; Adult; Affect; Animal Model; Anterior; Apical; Automobile Driving; Biological; Biological Assay; Biological Models; Cells; Chordata; Complex; Data; Data Set; Development; Developmental Process; Embryo; Epithelium; Evolution; Experimental Designs; Experimental Models; Foundations; Gastrula; Gene Expression; Gene Order; Genes; Genome; Genomics; Goals; Homeostasis; Hour; Knowledge; Learning; Ligands; MAPK8 gene; Mediating; Modeling; Molecular; Molecular Profiling; Neuroectoderm; Organ; Pathway interactions; Pattern; Positioning Attribute; Process; Prosencephalon; Regulator Genes; Research; Role; Sea Urchins; Series; Signal Pathway; Signal Transduction; Staging; Testing; Time; Tissues; Vertebrates; Visual Fields; Work; abstracting; activating transcription factor; base; beta catenin; comparative; design; extracellular; hemichordate; in vivo; in vivo Model; knock-down; member; neural patterning; neuroregulation; neurosensory; relating to nervous system; scaffold; spatiotemporal; transcription factor; transcriptome sequencing

Project Summary/Abstract The molecular mechanisms by which embryos pattern the early neuroectoderm along the anterior- posterior (AP) body axis and the mechanisms by which Wnt signaling networks govern multiple aspects of development and adult homeostasis are fundamental biological questions. However, much remains to be discovered about each of these questions, especially during the early development of deuterostome embryos where Wnt signaling is essential for anterior-posterior neuroectoderm patterning. We have recently discovered that 3 different, but interconnected, Wnt signaling pathways form a Wnt network that is essential for patterning the neuroectoderm along the anterior-posterior axis in early sea urchin embryos. Comparison of functional and expression studies among multiple deuterostome species (i.e., echinoderms, hemichordates, chordates), including vertebrates, strongly suggests that aspects of this Wnt network are conserved. The long-term goal of the studies in our lab is to systematically characterize the extracellular, intracellular and transcriptional players involved in the Wnt network governing early AP neuroectoderm patterning in the sea urchin. The objective of this R15 is to establish the transcriptional gene regulatory network (GRN) activated downstream of the Wnt network and perform initial functional studies to uncover how extracellular and intracellular Wnt modulators influence the activity of the network. The central hypothesis is that there are key interactions among the signaling pathways at the extracellular, intracellular, and transcriptional level. The rationale is that by first generating the transcriptional GRNs we can better understand how the extracellular and intracellular Wnt network are integrated in the AP neuroectoderm patterning GRN. Aim1 will uncover the transcription factors activated by the Wnt/JNK and Wnt/PKC signaling pathways during AP neuroectoderm patterning using information from differential screens comparing wild type embryos with Wnt/JNK and Wnt/PKC knockdown embryos. Functional gene perturbation studies will be performed to establish the transcriptional GRN scaffold and to define key interactions between the Wnt pathways at the transcriptional level. Aim 2 will use gene perturbation analyses on putative extracellular and intracellular Wnt modulators in order to better characterize the pathway members used in the Wnt/JNK and Wnt/PKC transduction pathways, to identify possible interactions among these modulators between the pathways, and to learn how these modulators affect the emerging GRN created in Aim1. The proposed research is significant because it will be one of the few systematic studies conducted to determine how these Wnt networks influence development in an in vivo model system. It will also provide the baseline for comparative functional studies of the GRN in other deuterostome model species, including vertebrates, thereby filling in large gaps in our knowledge of the evolution of early AP patterning mechanisms.

项目摘要/摘要 胚胎沿前部神经外胚层的早期神经外胚层的分子机制 后（AP）身体轴以及Wnt信号网络控制多个方面的机制 发展和成人稳态是基本的生物学问题。但是，还有很多事情要 发现了这些问题中的每一个，尤其是在Deuterostome的早期发展期间 Wnt信号传导对于前后神经外胚层构图至关重要的胚胎。我们有 最近发现3个不同但相互联系的Wnt信号通路形成了一个Wnt网络 对于早期海胆胚胎的前轴沿前后轴的神经外胚层构图是必不可少的。 比较多个氘代表物种之间的功能和表达研究（即棘皮动物， 半色调，弦弦），包括脊椎动物，强烈表明该Wnt网络的各个方面是 保守。我们实验室研究的长期目标是系统地表征细胞外的， 参与WNT网络的细胞内和转录播放器管理早期AP Neurocectoderm 海胆中的图案。 R15的目的是建立转录基因调节 网络（GRN）激活了Wnt网络的下游，并执行初始功能研究 发现细胞外和细胞内Wnt调节剂如何影响网络的活性。这 中心假设是在细胞外的信号通路之间存在关键相互作用， 细胞内和转录水平。理由是首先生成转录GRNS 我们可以更好地了解细胞外Wnt网络如何集成在AP中 Neurocectoderm构图GRN。 AIM1将发现Wnt/JNK激活的转录因子和 wnt/pkc信号传导途径在AP神经外胚层模式期间使用来自差异的信息 将野生型胚胎与Wnt/JNK和Wnt/PKC敲低胚胎进行比较的屏幕。功能基因 将进行扰动研究以建立转录GRN支架并定义密钥 转录级别的Wnt途径之间的相互作用。 AIM 2将使用基因扰动 对推定的细胞外和细胞内Wnt调节剂进行分析，以更好地表征 Wnt/JNK和Wnt/PKC转导途径中使用的途径成员，以识别可能 这些调节器之间的相互作用之间的相互作用，并了解这些调节剂如何影响 在AIM1中创建的新兴GRN。拟议的研究很重要，因为它将是少数 进行的系统研究是为了确定这些Wnt网络如何影响体内的发展 模型系统。它还将为GRN在其他方面的比较功能研究提供基线 氘代表模型物种，包括脊椎动物，从而填补了我们对 早期AP图案机制的演变。