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.

体细胞类型针对独特功能的特化可以说是生理学变化的最重要驱动力。 动物的复杂性。亚细胞结构的关键创新，包括开发一种专门的 分泌囊泡，增加了细胞的进化能力，并为细胞的创新提供了新的机会， 动物的多样化。例如，具有分泌凝胶形成粘液能力的细胞的出现 能够分离内部和外部组织区室，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， 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 测序技术的进步为研究基因组和转录组环境提供了一个窗口 来自不同生物体的多种细胞类型。虽然这些研究假设了这两种新的 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， 新基因如何连接到基因调控网络（GRNs）中以驱动新细胞类型的起源 仍然是我们对动物发育的认识中的一个关键空白。限制这一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是不可行的，这阻碍了我们翻译基因的能力。 将基因表达的观察转化为功能关系。一个强大的GRN演化建模系统 必须具有一个新的性状，具有可测量的表型，控制该性状的基因的识别网络，以及 遗传上易于控制的生物体进行实验测试。新的和多样的精液蛋白质的 果蝇符合所有这些特征，对这一系统的研究揭示了新的效应基因如何能够 快速获得影响生理和行为的基本功能。刺细胞-炸药，毒液- 丰富的刺细胞，使水母的刺-提供了许多相同的好处，果蝇， 模拟GRN演化。独特的形式和功能，刺突细胞包括不同的细胞类型谱系 仅见于刺胞动物（珊瑚、海葵和水母）。许多调节基因是必需的， 已经知道对于这种细胞类型来说，刺突细胞发育是新颖和独特的，提供了无与伦比的 有机会研究新的转录因子如何成为新的细胞类型的起源不可或缺。的 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， （2）海葵四种类型刺胞的形态特征表明， 组装一个独特的GRN子电路，通过比较密切相关的刺胞动物，和（3）开发一个 用于重定向细胞以获得新的分泌功能的技术。通过构建GRN， 在不同类型巢状细胞的形态发生中，我们可以精确地找到驱动自主细胞的必要基因。 在新的细胞类型中开发穿刺装置。因此，本研究提供了一个框架， 使刺突细胞适应其他新的功能，这可能有助于局部药物的新的递送机制。