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.

可以说，体细胞类型用于独特功能是生理的最重要驱动力 动物的复杂性。亚细胞结构的关键创新，包括开发专业的 秘书场地，提高了细胞的发展性，并为蜂窝创新提供了新的机会 动物的多样化。例如，具有秘密凝胶形成粘液的能力的细胞出现 启用了支持器官系统演化的内部和外部组织室的隔离。 尽管新细胞功能作为动物复杂性进化的来源，但基因组 促进新细胞类型的起源和多样化的机制仍然知之甚少。最近的 测序技术的进步为基因组和转录组环境提供了一个窗口 来自不同生物体的众多细胞类型。虽然这些研究假设了两者的作用 进化的基因和新建造的调节关系是细胞身份的关键要素，理解 新基因如何连接到基因调节网络（GRN）以驱动新细胞类型的起源 仍然是我们对动物发展知识的关键差距。限制该领域进展的一个挑战是 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 观察基因表达到功能关系中。建模GRN进化的强大系统 必须具有具有可测量表型的新颖性状，一个控制特征的基因网络，并且 可用于实验测试的遗传处理生物。小说和潜水的半流体蛋白 果蝇适合该系统中的所有这些特征和研究，揭示了新型效应基因如何如何 快速获得影响生理和行为的基本功能。 CNIDOCTES - 爆炸性，毒液 - 给水母刺痛的丰富刺穿细胞 - 提供与果蝇相同的好处 建模GRN进化。 CNIDOCTES在形式和功能上都具有独特性，包括细胞类型的潜水谱系 仅在Cnidarians（珊瑚，海葵和水母）中发现。许多调节基因 CNIDOCYTE的发育已知是新颖的，并且是这种细胞类型的独特性，提供了无与伦比的 研究新的转录因子如何成为新细胞类型的起源必不可少的机会。这 拟议的研究将实现三个目标；它将：（1）构建控制独特的基因网络 海洋长死杆菌中四种类型的cnidocyte的形态学，（2）揭示了逐步的 通过比较密切相关的cnidarians的比较，组装独特的GRN子电路，（3）发展 重定向细胞以获取新型秘书职能的技术。通过构建促进的GRN 在潜水员类型中的形态发生，我们可以查明驱动自主所需的基因 开发新细胞类型的穿孔设备。这是这项研究为 适应其他新型功能，可以为局部药物提供新的递送机制。