Dynamics of Primary Cilia Formation During Mammalian Development

项目摘要/摘要 初生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。 并专门对刺猬配体和其他信号做出反应。小儿科的异常 纤毛会导致肥胖、囊性肾病和影响大脑发育的出生缺陷， 骨架和心脏。虽然初级纤毛广泛分布在胚胎和成年组织中， 最近的研究表明，初生纤毛的形成受世系和阶段的调节。 从属进程。控制细胞型特异性初生纤毛的机制不是 为人所知。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 恢复或切除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。 在控制纤毛启动的调控网络中。特定蛋白质在其中的作用 包括RSG1、其他RGK蛋白和KIF24在内的网络将在突变小鼠身上得到验证 胚胎。将进行研究，以确定为什么小鼠体内有四种特定的细胞类型 胚胎缺乏初级纤毛：胚外内胚层(形成卵黄囊) 滋养外胚层(胎盘的重要组成部分)、成熟的肠道 上皮细胞和原始生殖细胞。调节动态增益的发育信号或 肠道和原始生殖细胞中的初级纤毛的丢失将被识别。很明显， 初级纤毛的组织特异性形成的许多调节因素尚未确定 将进行鉴定，以确定可以促进小鼠初级纤毛形成的基因 胚外内胚层干细胞，从不产生初生纤毛。

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.