Transcriptional regulation of multiciliate cell differentiation

多纤毛细胞分化的转录调控

• 批准号: 8026096
• 负责人: Christopher Robert Kintner
• 金额: $ 37.15万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 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/8026096
• 关键词: Transcriptional; regulation; multiciliate; cell; differentiation; Transcriptional; regulation; multiciliate; cell; differentiation

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，投射数百个纤毛的细胞，称为多重细胞，产生急剧的流体流动，可沿着腔表面运输生物材料。多核细胞填充呼吸道和生殖道，大脑的心室以及它们产生的流量对人类健康具有重要意义。尽管它们的重要性，但这些细胞在各种上皮中形成的基础的发展机制仍然未知。具体而言，多重细胞分化很可能在该单元格类型所需的转录代码的控制之下，但对此代码的性质知之甚少。为了解决这个问题，拟议的实验集中在一个新发现的基因，称为多粒蛋白。在初步实验中，基于其在X. laevis胚胎中的多层细胞中的高度限制表达中鉴定了多粒蛋白，但也在形成多层细胞的其他器官中表达。在功能测试中，多核细胞形成需要多粒蛋白，而当在胚胎的其他区域中进行敏化时，更明显地诱导异位多层细胞的形成。多粒蛋白编码一个功能所需的两个域的小蛋白质：类似于细胞周期调节剂中的中央盘绕型结构域，双子素和转录活性所需的第二个C末端结构域。因此，提出的实验将通过调节细胞周期进程和激活多核细胞分化所需的基因表达来确定多粒细胞是否促进了多核细胞的形成。另外，为了诱导多纤维细胞分化，多粒蛋白会促进锚定数百只纤毛所需的基础体的大规模组装。通过促进多元细胞独有的Centriole组装的新型途径，可以利用多粒细胞来洞悉这一知之甚少的过程。因此，多元素分析的结果将提供有关转录和细胞生物学事件的新信息，这些事件使上皮祖细胞可以转变为多细胞。这些信息可能会加快从诱导或胚胎的干细胞中生成多细胞细胞的方法的进步，并通过转分化在再生过程中促进其他细胞类型的多层细胞的形成。 公共卫生相关性：多细胞通过在脑，肺和生殖道中产生液体流动来在人类健康中起重要作用，但是对介导这些细胞在胚胎发生过程中介导这些细胞形成的机制知之甚少。为了研究这些机制，拟议的研究将集中在一种称为多粒蛋白的新基因上，该基因既需要促进多层细胞的形成，既是必要又足够的。分析多粒蛋白功能将有助于影响纤毛上皮症的人类疾病的诊断和治疗，例如在原发性纤毛运动障碍和Kartegener综合征期间发生的纤毛缺陷。