Dynamics of Primary Cilia Formation During Mammalian Development

哺乳动物发育过程中初级纤毛形成的动态

• 批准号: 10063527
• 负责人: ALEXANDRA L. JOYNER
• 金额: $ 55.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063527
• 关键词: Adult; Affect; Brain; Candidate Disease Gene; Cell Culture Techniques; Cell Cycle; Cell Line; Cells; Centrioles; Chemicals; Cilia; Cilium Microtubule; Congenital Abnormality; Cultured Cells; Cystic Kidney Diseases; Data; Development; Disease; Embryo; Endoderm; Erinaceidae; Excision; Family; Fetus; Genes; Genetic; Genetic Diseases; Goals; Gonadal structure; Guanosine Triphosphate Phosphohydrolases; Heart; Human Development; Human Genetics; Intestines; Lead; Ligands; Mammalian Cell; Mechanics; Microtubules; Mothers; Mus; Mutant Strains Mice; Obesity; Organelles; Phenotype; Placenta; Pregnancy; Process; Proteins; Proteomics; Regulation; Resolution; Role; Signal Transduction; Skeleton; Stimulus; Structure of primordial sex cell; Surface; Testing; Tissues; Ursidae Family; Validation; Visceral; Work; Yolk Sac; adult stem cell; base; cell type; cilium biogenesis; experimental study; genetic analysis; genome wide screen; hedgehog signal transduction; human disease; in vivo; intestinal epithelium; kinetosome; member; migration; mouse genetics; novel strategies; prevent; response; restoration; stem cells; therapy development; tool; tumor

Project Summary/Abstract Primary cilia are microtubule-based organelles that extend from the surface of mammalian cells and are specialized to respond to Hedgehog ligands and other signals. Abnormalities in primary cilia cause obesity, cystic kidney disease, and birth defects that affect development of the brain, skeleton and heart. Although primary cilia are widely distributed in embryonic and adult tissues, recent studies showed that the formation of primary cilia is regulated by lineage- and stage- dependent processes. The mechanisms that control cell-type specific primary cilia are not known. The goal of this project is to define the mechanisms that regulate primary cilia formation in specific tissues of the mouse embryo, with the long-term goal of developing therapies to restore or ablate cilia to treat human disease. Studies carried out in cells derived from mouse embryos will define the roles of specific proteins in the regulatory network that controls cilia initiation. The functions of specific proteins in that network, including RSG1, other RGK proteins and KIF24, will be validated in mutant mouse embryos. Studies will be carried out to determine why four specific cell types in the mouse embryo lack primary cilia: the extraembryonic endoderm (which contributes to the yolk sac of the fetus), the trophectoderm (an essential component of the placenta), the mature intestinal epithelium, and primordial germ cells. Developmental signals that regulate the dynamic gain or loss of primary cilia in the intestine and primordial germ cells will be identified. As it is clear that many regulators of tissue-specific formation of primary cilia have yet to be identified, screens will be carried out to identify genes that can promote formation of primary cilia in mouse extraembryonic endoderm stem cells, which never bear primary cilia.

项目总结/摘要 初级纤毛是从哺乳动物细胞表面延伸出来的基于微管的细胞器 并专门对Hedgehog配体和其他信号作出反应。小学辍学 纤毛导致肥胖、囊性肾病和影响大脑发育的出生缺陷， 骨骼和心脏虽然初级纤毛广泛分布在胚胎和成体组织中， 最近的研究表明，初级纤毛的形成受谱系和阶段的调节， 依赖过程。控制细胞类型特异性初级纤毛的机制不是 知道的这个项目的目标是确定调节初级纤毛形成的机制 在小鼠胚胎的特定组织中，长期目标是开发治疗方法， 恢复或消融纤毛以治疗人类疾病。 在小鼠胚胎细胞中进行的研究将确定特定蛋白质的作用 在控制纤毛起始的调节网络中。其中特定蛋白质的功能 包括RSG 1、其他RGK蛋白和KIF 24的网络将在突变小鼠中验证 胚胎将进行研究，以确定为什么小鼠中的四种特定细胞类型 胚胎缺乏初级纤毛：胚外内胚层（有助于卵黄囊的形成） 胎儿），滋养外胚层（胎盘的重要组成部分），成熟的肠 上皮和原始生殖细胞。调节动态增益的发育信号， 将鉴定肠中初级纤毛和原始生殖细胞的损失。很明显， 初级纤毛的组织特异性形成的许多调节剂还有待鉴定、筛选 将进行鉴定基因，可以促进形成初级纤毛在小鼠 胚胎外内胚层干细胞，从不承担初级纤毛。