Unveiling the evolution of neural differentiation mechanisms in animals: a study of the structure and function of the POU-IV/Brn-3 gene regulatory network in Cnidaria.

揭示动物神经分化机制的进化：刺胞动物 POU-IV/Brn-3 基因调控网络的结构和功能研究。

• 批准号: 1931154
• 负责人: Nagayasu Nakanishi
• 金额: $ 76.5万
• 依托单位: University of Arkansas
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1931154&HistoricalAwards=false
• 关键词: Unveiling; evolution; neural; differentiation; mechanisms

Understanding how nervous systems emerged and diversified over evolutionary time is a fundamental problem in biology. This research project will use sea anemones, whose ancestors split off from all other animal lineages over 600 million years ago, to reconstruct the deep evolutionary history of neural development in animals. The resultant knowledge will contribute to the understanding of nervous system evolution in two ways: (1) it will provide fundamental insights into developmental mechanisms that were critical for the origin of nervous systems over 600 million years ago, and 2) it will provide new information about how these mechanisms have diversified in the intervening time period. This project will additionally broaden participation of underrepresented minorities in STEM by actively involving minority undergraduate students directly in research through participation in the Undergraduate Student Mentoring Program of Arkansas INBRE (IDeA Network of Biomedical Research Excellence). Furthermore, the research will strengthen both the research and educational environments at the University of Arkansas by using a unique, non-traditional animal model system that makes it easy give students first-hand experience with cutting-edge biological technologies such as CRISPR-Cas9 genome editing, Next Generation Sequencing, and confocal microscopy. The research will advance fundamental knowledge about the origin and evolution of nervous systems, as well as benefit society through basic science research and education. In bilaterian animals (e.g. mice, worms and flies), the class IV POU homeodomain transcription factor (POU-IV or Brn-3) plays an evolutionarily conserved role in regulating neural subtype differentiation and maintenance. However, it is unclear whether the conservation of POU-IV function extends beyond Bilateria, or whether divergent, novel regulatory mechanisms exist in non-bilaterian animal groups with nervous systems such as Cnidaria (e.g. jellyfish, corals and sea anemones) – the sister group of Bilateria. To address this problem, the research will dissect the structure and function of the POU-IV gene regulatory network in the cnidarian sea anemone Nematostella vectensis. Specifically, this project will focus on 1) defining neural subtypes specified by POU-IV by combining in-depth gene expression analyses with gene function analyses via CRISPR-Cas9-mediated genome editing, and 2) dissecting the structure of the POU-IV gene regulatory network underpinning neural fate specification by combining gene function perturbation, ChIP-seq, and transcriptome analyses.This project is jointly funded by the Organization Program of the Neural Systems Cluster, and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

了解神经系统如何在进化过程中出现和多样化是生物学的一个基本问题。海葵的祖先在6亿多年前从所有其他动物谱系中分离出来，该研究项目将利用海葵来重建动物神经发育的深层进化史。由此产生的知识将有助于从两个方面理解神经系统的进化：(1)它将提供对6亿年前神经系统起源至关重要的发育机制的基本见解；(2)它将提供关于这些机制在中间时期如何多样化的新信息。该项目还将通过参与阿肯色州INBRE （IDeA生物医学研究卓越网络）的本科生指导计划，积极让少数族裔本科生直接参与研究，从而扩大代表性不足的少数族裔在STEM领域的参与。此外，该研究将通过使用独特的非传统动物模型系统，加强阿肯色大学的研究和教育环境，使学生轻松获得尖端生物技术的第一手经验，如CRISPR-Cas9基因组编辑，下一代测序和共聚焦显微镜。这项研究将推进有关神经系统起源和进化的基础知识，并通过基础科学研究和教育造福社会。在双侧动物（如小鼠、蠕虫和苍蝇）中，IV类POU同源结构域转录因子（POU-IV或Brn-3）在调节神经亚型分化和维持中起着进化保守的作用。然而，目前尚不清楚poui - iv功能的保护是否延伸到双侧门动物之外，或者是否在具有神经系统的非双侧动物类群中存在不同的新调节机制，如双侧门的姐妹类群刺胞动物（如水母、珊瑚和海葵）。为了解决这一问题，本研究将对刺胞海葵（Nematostella vectensis）中pu - iv基因调控网络的结构和功能进行剖析。具体而言，该项目将侧重于：1)通过crispr - cas9介导的基因组编辑，将深度基因表达分析与基因功能分析相结合，定义由pu - iv指定的神经亚型；2)通过结合基因功能扰动、ChIP-seq和转录组分析，剖析支持神经命运规范的pu - iv基因调控网络结构。该项目由神经系统集群组织计划和刺激竞争研究的既定计划（EPSCoR）共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。