The ancestry of animal cell differentiation and pluripotency

动物细胞分化和多能性的祖先

• 批准号: 10501885
• 负责人: David Scott Booth
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501885
• 关键词: Animals; Biological Models; Biology; Cell Differentiation process; Characteristics; Cues; Cytology; Data; Development; Environment; Evolution; Foundations; Gene Delivery; Genes; Genetic; Human Biology; Methods; Mission; Modeling; Molecular; Molecular Genetics; Pathway interactions; Phenotype; Postdoctoral Fellow; RNA-Binding Proteins; Regulatory Pathway; Research; Surveys; Work; base; cell type; functional genomics; gene function; genome editing; genome wide screen; novel; pluripotency; programs; tool

ABSTRACT Animals build their multicellular bodies with diverse types of cells that perform and integrate distinct functions. Animals, however, are not unique in their capacity to generate distinct cell types. In fact, their closest living relatives, a group of aquatic, unicellular, bacterivorous protists called choanoflagellates, detect biotic and abiotic cues to differentiate into phenotypically and functionally distinct cell types in different environments. Choanoflagellates also possess critical genes that regulate animal cell differentiation during development, supporting the hypothesis that cell differentiation mechanisms evolved prior to the origin of animals and became integral in animal and choanoflagellate biology. Although nearly 800 million years of animal evolution has shaped human biology since we last shared a common ancestor with choanoflagellates, the commonalities in genetic toolkits and cytological characteristics indicate that choanoflagellates have tremendous potential as microeukaryotic models to investigate the core functions of genes that regulate cell differentiation. During my postdoc, I pioneered the first methods for gene delivery and genome editing in the choanoflagellate Salpingoeca rosetta to realize its full potential as a model system. My lab continues to propel those methods for the discovery of the molecular mechanisms that drive environmentally-triggered cell differentiation in S. rosetta. This proposal supports our research mission by using the molecular tools I developed to dissect putative regulatory pathways that emerge from functional genomic surveys. In particular, we focus on homologs of RNA-binding proteins that form the animal germline and and/or maintain pluripotency. Moreover, we strive to develop our nascent genetic tools into scalable, easy methods that enable genome-wide screens of cell differentiation regulators. Overall, this work will contribute a new, functional comparison to illuminate the origin and evolution of cell differentiation pathways in choanoflagellates and animals, which I anticipate will uncover core functions of biomedically important genes that originated before choanoflagellates and animals diverged.

摘要 动物用不同类型的细胞来构建它们的多细胞体， 功能协调发展的然而，动物产生不同细胞类型的能力并不独特。事实上，他们最亲密的 活着的亲戚，一群水生的，单细胞的，食菌的原生生物称为choanoflagellates，检测生物和 在不同的环境中分化成表型和功能不同的细胞类型的非生物线索。 领鞭毛虫还具有在发育过程中调节动物细胞分化的关键基因， 支持细胞分化机制在动物起源之前进化的假设， 成为了动物和后领鞭毛虫生物学中不可或缺的部分。 尽管自从我们上次分享了一个新的物种以来，近8亿年的动物进化已经塑造了人类生物学。 与领鞭毛虫的共同祖先，遗传工具包和细胞学特征的共同点 表明领鞭毛虫作为微真核生物模型具有巨大的潜力， 调节细胞分化的基因的功能。在我的博士后期间，我开创了第一个基因检测方法， 传递和基因组编辑在choanoflagellate Salpingoeca rosetta实现其作为模型的全部潜力 系统我的实验室继续推动这些方法，以发现驱动 环境触发的S.罗塞塔。这项建议支持我们的研究使命， 我开发的分子工具是为了剖析从功能基因组中出现的假定的调控途径， 调查。特别是，我们专注于形成动物生殖系和/或哺乳动物生殖细胞的RNA结合蛋白的同源物。 保持多能性。此外，我们努力将我们新生的遗传工具发展成可扩展的，简单的方法， 使全基因组筛选细胞分化调节因子成为可能。总的来说，这项工作将有助于一个新的，功能 比较，以阐明在choanoflagellates细胞分化途径的起源和进化， 我预计这将揭示生物医学重要基因的核心功能，这些基因起源于 领鞭毛虫和其他动物分道扬镳。