Gene Regulation and the Origin of New Cell Types

基因调控和新细胞类型的起源

• 批准号: 10705692
• 负责人: Leslie S Babonis
• 金额: $ 39.25万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705692
• 关键词: Affect; Animal Model; Animals; Area; Behavior; Biological Models; Cell Lineage; Cell physiology; Cells; Characteristics; Cnidaria; Development; Developmental Biology; Drosophila genus; Elements; Environment; Evolution; Gel; Gene Expression; Gene Expression Regulation; Genes; Genomics; Goals; Individual; Jellyfish; Knowledge; Laboratory Organism; Measurable; Modeling; Molecular; Morphogenesis; Morphology; Mucous body substance; Nematostella; Organism; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Process; Proteins; Regulator Genes; Research; Research Project Grants; Role; Sea Anemones; Secretory Vesicles; Seminal fluid; Somatic Cell; Source; Sting Injury; Subcellular structure; System; Techniques; Technology; Testing; Tissues; Translating; Venoms; body system; cell type; coral; gene network; gene regulatory network; genetic manipulation; innovation; novel; segregation; trait; transcription factor; transcriptomics

The specialization of somatic cell types for unique functions is arguably the most important driver of physiological complexity in animals. Key innovations in subcellular structure, including the development of a specialized secretory vesicle, increased the evolvability of cells and provided new opportunities for cellular innovation during the diversification of animals. For example, the emergence of cells with the capacity to secrete gel-forming mucus enabled segregation of internal and external tissue compartments facilitating the evolution of organ systems. Despite the value of novel cell function as a source for the evolution of animal complexity, the genomic mechanisms promoting the origin and diversification of new cell types remain poorly understood. Recent advances in sequencing technologies have provided a window into the genomic and transcriptomic environments of numerous cell types from diverse organisms. While these studies have hypothesized roles for both newly evolved genes and newly constructed regulatory relationships as critical elements of cell identity, understanding how new genes get wired into gene regulatory networks (GRNs) to drive the origin of new cell types remains a key gap in our knowledge of animal development. One challenge limiting progress in this area is that it is still not feasible to manipulate gene expression in many animal models, hampering our ability to translate observations of gene expression into functional relationships. A powerful system for modeling GRN evolution must have a novel trait with a measurable phenotype, an identified network of genes controlling the trait, and a genetically tractable organism for experimental testing. The novel and diverse seminal fluid proteins of Drosophila fit all these characteristics and studies in this system have revealed how novel effector genes can rapidly acquire essential functions affecting both physiology and behavior. Cnidocytes – the explosive, venom- rich piercing cells that give jellyfish their sting – offer many of the same benefits as Drosophila for modeling GRN evolution. Unique in both form and function, cnidocytes comprise a diverse lineage of cell types found only in cnidarians (corals, sea anemones, and jellyfish). Many of the regulatory genes necessary for cnidocyte development are already known to be novel and unique to this cell type, providing an unparalleled opportunity to study how new transcription factors become indispensable for the origin of new cell types. The proposed research will achieve three goals; it will: (1) construct the network of genes controlling the unique morphologies of the four types of cnidocyte in the sea anemone Nematostella vectensis, (2) reveal the step-wise assembly of a unique GRN subcircuit through comparisons of closely related cnidarians, and (3) develop a technique for redirecting cells to acquire novel secretory functions. By constructing the GRN that promotes morphogenesis in diverse cnidocyte types, we can pinpoint the genes necessary to drive autonomous development of the piercing apparatus in new cell types. Thus, this research provides a framework for adapting cnidocytes for other novel functions that could contribute to new delivery mechanisms for topical drugs.

体细胞类型的独特功能的专门化是有争议的，这是生理学最重要的驱动因素 动物亚细胞结构的关键创新，包括开发专门的亚细胞结构。 分泌囊泡，增加了细胞的进化能力，为细胞创新提供了新的机会 例如，具有分泌凝胶形成粘液能力的细胞的出现。 实现内部和外部组织隔室的分离，促进器官系统的进化。 尽管新的细胞功能作为动物复杂性进化的来源具有价值，但基因组 促进新细胞类型起源和多样化的机制目前仍知之甚少。 测序技术的进步为了解基因组和转录组环境提供了一个窗口 虽然这些研究已经探索了来自不同生物体的多种细胞类型的新作用。 进化的基因和新构建的调控关系作为细胞身份的关键要素，理解 新基因如何连接到基因调控网络（GRN）以驱动新细胞类型的起源 限制这一领域进展的一个挑战仍然是我们对动物发育的了解中的一个关键差距。 在许多动物模型中操纵基因表达仍然不可行，这阻碍了我们翻译的能力 将基因表达观察转化为功能关系的强大系统，用于模拟 GRN 进化。 必须具有具有可测量表型的新性状、控制该性状的已识别基因网络以及 用于实验测试的遗传易处理的生物体。 果蝇符合所有这些特征，并且对该系统的研究揭示了新的效应基因如何能够 迅速获得影响生理和行为的基本功能——具有爆炸性、毒液的细胞。 丰富的刺穿细胞使水母能够蜇伤——提供许多与果蝇相同的好处 模拟 GRN 的进化。 仅在刺胞动物（珊瑚、海葵和水母）中发现许多必需的调节基因。 众所周知，刺胞细胞的发育对于这种细胞类型来说是新颖且独特的，提供了无与伦比的 有机会研究新的转录因子如何对于新细胞类型的起源变得不可或缺。 拟议的研究将实现三个目标；（1）构建控制独特性的基因网络。 海葵 Nematostella vectensis 中四种刺胞细胞的形态，(2) 揭示了逐步 通过比较密切相关的刺胞动物来组装独特的 GRN 子电路，以及 (3) 开发 通过构建促进细胞重新定向以获得新的分泌功能的技术。 不同类型的腔细胞的形态发生，我们可以查明驱动自主所需的基因 因此，这项研究为新细胞类型的穿刺装置的开发提供了一个框架。 使刺胞细胞适应其他新功能，这可能有助于局部药物的新递送机制。