A new animal model to elucidate mechanisms of gene regulation and embryonic patterning

阐明基因调控和胚胎模式机制的新动物模型

• 批准号: 10798810
• 负责人: Caroline B Albertin
• 金额: $ 25万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798810
• 关键词: Address; Animal Model; Animals; Biological Models; Biology; Body Regions; Cephalopoda; Characteristics; Chromosomes; Complement; Data; Defect; Developmental Gene; Developmental Process; Ear; Elements; Embryo; Embryonic Development; Exhibits; Face; Family; Gene Expression Regulation; Gene Family; Genital; Genitalia; Genome; Homeobox Genes; Human; Human Development; Invertebrates; Knock-out; Knowledge; Limb structure; Malignant Neoplasms; Mammals; Nematoda; Octopus; Pattern; Phenotype; Play; Regulation; Resources; Squid; Structure; Vertebrates; Work; fly; genetic manipulation; genome-wide; human disease; insight; malformation; neural; programs; spine bone structure; tool; transcription factor; transcriptomics; whole genome

Project Summary Hox genes serve as critical regulators of developmental processes. Disruption of their function during embryogenesis results in dramatic “homeotic” phenotypes where regions of the body are transformed from one identity to another. In humans, these disruptions can lead to malformation of the face, ears, limbs, and genitalia, as well as neural defects and cancer. In many animal genomes, the Hox genes are found in clusters: in vertebrates, these clusters are compact, while those of invertebrates are more loosely arranged or fragmented. While still poorly understood, the structure of the Hox cluster is hypothesized to be important in regulating their deployment. However, this is difficult to study in vertebrates as their genomes encode multiple Hox clusters that are the result of whole genome duplications. While invertebrates typically have a single complement of Hox genes, many invertebrate Hox clusters are disrupted, including those found in the classic invertebrate model systems like flies and nematodes. To address this deficit, we have developed resources and tools for studying cephalopod molluscs (squid and octopus), including chromosome-scale genome assemblies, extensive transcriptomics, and tools for gene manipulation. Through this work, we have found that cephalopods have a single, intact, but massively expanded Hox cluster. In fact, they encode the largest Hox clusters yet described – the squid Hox cluster is two orders of magnitude larger than those found in humans. Conservation of the Hox cluster in cephalopods is particularly striking given that their genomes are otherwise highly rearranged relative to other animals. Notably, we have found that cephalopod Hox genes exhibit the canonical, collinear nested domains of expression, suggesting that elements of the ancestral regulatory program are retained in cephalopods despite the dramatic increase in cluster size. Surprisingly, our preliminary knockout data suggest that loss of a Hox gene results in the absence, rather than the transformation, of body regions. These results - the first functional analysis of Hox genes in a mollusc - point to a fundamentally different mode of action than the homeotic transformations characteristic of overtly segmented animals like flies and humans. Understanding differences between the massive cephalopod Hox clusters and the more compact arrangement found in vertebrates will provide fundamental insights concerning the regulation of these body plan transcription factors across diverse animal species, including humans. This project is therefore poised to provide transformational insights into the biology of Hox genes, which play key roles in human development and disease, and contribute to our fundamental knowledge of how pattern is established in embryogenesis.

项目摘要 Hox基因是发育过程的重要调控因子。在执行任务期间， 胚胎发生导致戏剧性的“同源异型”表型， 另一个身份。在人类中，这些破坏可能导致面部、耳朵、四肢和大脑的畸形。 生殖器，以及神经缺陷和癌症。在许多动物基因组中，Hox基因被发现成簇： 在脊椎动物中，这些集群是紧凑的，而无脊椎动物的集群则排列得更松散， 支离破碎虽然仍然知之甚少，但Hox星系团的结构被假设为在 规范其部署。然而，这在脊椎动物中很难研究，因为它们的基因组编码多个 Hox簇是全基因组复制的结果。虽然无脊椎动物通常只有一个 由于Hox基因的互补，许多无脊椎动物的Hox簇被破坏，包括那些在经典的 无脊椎动物模型系统，如苍蝇和线虫。 为了解决这一问题，我们开发了研究头足类软体动物（鱿鱼和 章鱼），包括染色体规模的基因组组装，广泛的转录组学，和基因工具， 操纵通过这项工作，我们发现头足类动物有一个单一的，完整的，但大量的 扩展Hox集群。事实上，它们编码了迄今为止所描述的最大的Hox簇-鱿鱼Hox簇， 比人类大两个数量级头足类中Hox簇的保护是 特别引人注目的是，它们的基因组相对于其他动物而言是高度重排的。值得注意的是， 我们已经发现头足类Hox基因表现出典型的、共线的嵌套表达结构域， 这表明，祖先的调控程序的元素保留在头足类动物，尽管戏剧性的， 增加集群规模。令人惊讶的是，我们的初步敲除数据表明，Hox基因的丢失导致 身体区域的缺失，而不是转变。这些结果-Hox的第一个功能分析 软体动物中的基因-指向一种与同源异型转化根本不同的作用模式 具有明显分节的动物的特征，如苍蝇和人类。了解不同 大型头足类Hox集群和脊椎动物中发现的更紧凑的排列将提供 关于这些身体计划转录因子在不同动物中的调节的基本见解 物种，包括人类。因此，该项目准备为生物学提供变革性的见解 Hox基因，在人类发育和疾病中发挥关键作用，并有助于我们的基本 关于胚胎发生中模式如何建立的知识。