Transcriptional regulation of multiciliate cell differentiation

多纤毛细胞分化的转录调控

基本信息

批准号：
8150383
负责人：
Christopher Robert Kintner
金额：
$ 36.78万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150383
关键词：
Address Affect Amino Acids Binding Biocompatible Materials Biological Biology Brain C-terminal Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Fate Control Cells Centrioles Cerebral Ventricles Cilia Code Coiled-Coil Domain Complex DNA Data Defect Development Diagnosis Elements Embryo Embryonic Development Epithelial Epithelial Cells Epithelium Event Geminin Gene Expression Genes Genetic Genetic Transcription Goals Health Human Light Lung Maps Mediating Modeling Natural regeneration Nature Organ Pathway interactions Phenotype Play Primary Ciliary Dyskinesias Process Proteins Recruitment Activity Research Response Elements Role Skin Specialized Epithelial Cell Specific qualifier value Speed Stem cells Structure Surface Syndrome Testing Transcriptional Regulation Tubulin Vertebrates base body system cell type feeding fluid flow gain of function gene discovery human disease insight kinetosome lung development mutant novel precursor cell progenitor promoter public health relevance reproductive research study respiratory tool transcription factor transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): In many organ systems, cells projecting hundreds of beating cilia, called multiciliate cells, produce a vigorous fluid flow that transports biological materials along luminal surfaces. Multiciliate cells populate the respiratory and reproductive tracts, and the ventricles of the brain, and the flow they produce has significant implications for human health. Despite their importance, the developmental mechanisms that underlie the formation of these cells in diverse epithelia are still unknown. Specifically, multiciliate cell differentiation is likely to be under the control of a transcriptional code that is required for this cell type to form, but little is known about the nature of this code. To address this issue, the proposed experiments focus on a newly discovered gene, called Multicilin. Multicilin was identified in preliminary experiments based on its highly restricted expression in multiciliate cells in X. laevis embryos, but is also expressed in other organs that form multiciliate cells. In functional tests, Multicilin is required for multiciliate cells to form, and more remarkably will induce the formation of ectopic multiciliate cells when misexpressed in other regions of the embryo. Multicilin encodes a small protein with two domains required for function: a central coiled-coil domain similar to the one found in the cell cycle regulator, Geminin, and a second C-terminal domain required for transcriptional activity. Thus, the proposed experiments will determine whether Multicilin promotes the formation of multiciliate cells by both modulating cell cycle progression and by activating gene expression required for multiciliate cell differentiation. In addition, in order to induce multiciliate cell differentiation, Multicilin promotes the large-scale assembly of basal bodies required to anchor hundreds of cilia. By promoting novel pathways of centriole assembly that are unique to multiciliate cells, Multicilin can be exploited to gain insight into this poorly understood process. Thus, the results from the analysis of Multicilin will provide new information about the transcriptional and cell biological events that allow epithelial progenitors to turn into multiciliate cells. This information will likely speed progress in devising approaches to generate multiciliate cells from stem cells, either induced or embryonic, and for promoting the formation of multiciliate cells from other cell types during regeneration via transdifferentiation. PUBLIC HEALTH RELEVANCE: Multiciliate cells play important roles in human health by generating fluid flow in the brain, lung and reproductive tract, but the mechanisms that mediate the formation of these cells during embryogenesis are poorly understood. To study these mechanisms, the proposed research will focus on a new gene, called Multicilin, which is both necessary and sufficient to promote multiciliate cell formation. Analyzing Multicilin function will aid in the diagnosis and treatment of human disease that affect ciliated epithelia, such as the ciliary defects that occurs during primary ciliary dyskinesia and Kartegener's syndrome.

描述（由申请人提供）：在许多器官系统中，投射数百个跳动纤毛的细胞（称为多纤毛细胞）产生强劲的流体流，沿着管腔表面运输生物材料。多纤毛细胞分布在呼吸道、生殖道以及脑室中，它们产生的流量对人类健康具有重大影响。尽管它们很重要，但这些细胞在不同上皮细胞中形成的发育机制仍然未知。具体而言，多纤毛细胞分化可能受到该细胞类型形成所需的转录密码的控制，但人们对该密码的性质知之甚少。为了解决这个问题，拟议的实验重点关注一种新发现的基因，称为 Multicilin。 Multicilin 在初步实验中根据其在非洲爪蟾胚胎的多纤毛细胞中的高度限制性表达而被鉴定，但它也在形成多纤毛细胞的其他器官中表达。在功能测试中，多纤毛细胞的形成需要多纤毛蛋白，更值得注意的是，当在胚胎的其他区域错误表达时，它会诱导异位多纤毛细胞的形成。 Multicilin 编码一种小蛋白，具有功能所需的两个结构域：一个与细胞周期调节因子 Geminin 中发现的相似的中央卷曲螺旋结构域，以及转录活性所需的第二个 C 末端结构域。因此，拟议的实验将确定 Multicilin 是否通过调节细胞周期进程和激活多纤毛细胞分化所需的基因表达来促进多纤毛细胞的形成。此外，为了诱导多纤毛细胞分化，Multicilin 促进锚定数百个纤毛所需的基体的大规模组装。通过促进多纤毛细胞特有的中心粒组装的新途径，可以利用 Multicilin 深入了解这一鲜为人知的过程。因此，Multicilin 的分析结果将提供有关使上皮祖细胞转变为多纤毛细胞的转录和细胞生物学事件的新信息。这些信息可能会加速设计从诱导干细胞或胚胎干细胞产生多纤毛细胞的方法的进展，以及在通过转分化的再生过程中促进其他细胞类型形成多纤毛细胞的方法。公共健康相关性：多纤毛细胞通过在大脑、肺和生殖道中产生液体流动，在人类健康中发挥着重要作用，但在胚胎发生过程中介导这些细胞形成的机制却知之甚少。为了研究这些机制，拟议的研究将集中于一种名为 Multicilin 的新基因，它对于促进多纤毛细胞的形成既是必要的也是充分的。分析 Multicilin 功能将有助于诊断和治疗影响纤毛上皮的人类疾病，例如原发性纤毛运动障碍和卡特格纳综合征期间发生的纤毛缺陷。