Evolution of the gene regulatory network for pharyngeal segmentation

咽分割基因调控网络的进化

• 批准号: 2054340
• 负责人: Daniel Medeiros
• 金额: $ 84.55万
• 依托单位: University of Colorado at Boulder
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2054340&HistoricalAwards=false
• 关键词: Evolution; gene; regulatory; network; pharyngeal

The bones and cartilages of the jaws, face, neck, and inner ear develop from embryonic structures called pharyngeal arches. Defects in pharyngeal arch development underlie many human birth defects. The pharyngeal arches of non-human vertebrates also form most of the head skeleton, including the gills of aquatic vertebrates. Though the pharyngeal arches form similarly in all vertebrates, they ultimately give rise very different head skeletons in different vertebrate groups. How such variation is achieved using the same basic set of genes and developmental processes is unclear. The project seeks to elucidate the aspects of pharyngeal arch development shared by all vertebrates, and those that differ between major groups. This information will serve two purposes. First, it will shed light on the genetic and developmental changes that led to the evolution of new vertebrate groups. Second, it will help identify the causes of genetic and environmentally-induced disruptions human craniofacial development. This project will also support the creation and staffing of a large, interactive zoo exhibit entitled “Hidden Links: Discovering Your Inner Invertebrate”, that will be seen by over 300,000 visitors annually, including 57,000 grade school students. The exhibit will expose visitors to key biological concepts such as evolution, phylogenetics, genetics, segmentation, and development. The work will also support the training of three Ph.D. students, several undergraduates, and provide research projects for 1-2 high school students per year.Robust, paired pharyngeal arches (PAs) are a defining feature of vertebrates. PAs form most of the breathing and feeding structures of the vertebrate “new head”, and variation in PA number and derivatives is a major contributor to vertebrate morphological diversity. Though PAs play a key role in shaping the vertebrate head, the genetic mechanisms driving PA development are poorly understood. Even less is known about how they have been altered during evolution to yield different oropharyngeal phenotypes. The PAs form in an anterior-to-posterior sequence when bilateral endodermal outpocketings called pharyngeal pouches (PPs) contact overlying ectoderm. Studies in zebrafish, medaka, and mouse have identified a small, conserved set of genes that drives PP development in model vertebrates. However, how these genes interact differs between teleosts and mouse. When during evolution these gene regulatory differences arose, and if they contribute to differences in oropharyngeal morphology, is unknown. To better understand the genetic bases of vertebrate oropharyngeal diversity, this work will reconstruct the ancestral gene regulatory network for PP/PA development (the PP GRN). This information will then be used to deduce how and why the PP GRN has been altered in modern lineages. To do this, the PP GRN of the sea lamprey, Petromyzon marinus, and the frog, Xenopus laevis will be interrogated using CRISPR/Cas9 mutagenesis and pharmacological perturbations.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.

颌骨、面部、颈部和内耳的骨骼和软骨是从称为咽弓的胚胎结构发育而来的。咽弓发育缺陷是许多人类出生缺陷的基础。非人类脊椎动物的咽弓也形成了大部分的头部骨骼，包括水生脊椎动物的鳃。虽然所有脊椎动物的咽弓形成相似，但它们最终在不同的脊椎动物群中形成了非常不同的头部骨骼。这种变异是如何利用相同的基本基因组和发育过程实现的尚不清楚。该项目旨在阐明所有脊椎动物共有的咽弓发育方面，以及主要群体之间的差异。 这些信息将用于两个目的。 首先，它将阐明导致新脊椎动物群体进化的遗传和发育变化。 其次，它将有助于确定遗传和环境引起的人类颅面发育中断的原因。该项目还将支持一个名为“隐藏的联系：发现你内心的无脊椎动物”的大型互动动物园展览的创建和人员配备，每年将有300 000多名游客参观，其中包括57 000名小学生。 展览将向参观者展示关键的生物学概念，如进化，遗传学，遗传学，分割和发展。 这项工作还将支持培养三名博士。学生，几个本科生，每年为1-2名高中生提供研究项目。健壮的成对咽弓（PA）是脊椎动物的一个定义特征。PA形成了脊椎动物“新头”的呼吸和进食结构，PA数量和衍生物的变化是脊椎动物形态多样性的主要贡献者。虽然PA在塑造脊椎动物头部中起着关键作用，但驱动PA发育的遗传机制知之甚少。关于它们在进化过程中如何被改变以产生不同的口咽表型，我们知道的更少。当双侧内胚层外囊（称为咽囊（PP））接触上覆的外胚层时，PA以前到后的顺序形成。 在斑马鱼、青鳉和小鼠中的研究已经确定了一组小型保守的基因，这些基因驱动模型脊椎动物中的PP发育。然而，这些基因如何相互作用在硬骨鱼和小鼠之间是不同的。在进化过程中，这些基因调控差异何时出现，以及它们是否有助于口咽形态的差异，都是未知的。为了更好地了解脊椎动物口咽多样性的遗传基础，这项工作将重建PP/PA发育的祖先基因调控网络（PP GRN）。 这些信息将被用来推断PP GRN在现代血统中是如何以及为什么被改变的。 为此，将使用CRISPR/Cas9诱变和药理学干扰技术对七鳃鳗、海洋巨鳗和非洲爪蟾的PP GRN进行研究。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。