Structure and function of a novel population of regenerating ependymal cells

新型再生室管膜细胞群的结构和功能

基本信息

批准号：
10400197
负责人：
Arturo Alvarez-Buylla
金额：
$ 44.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10400197
关键词：
Ablation Address Adult Affect Age Aging Apical Apoptosis Apoptotic Area Basal Cell Brain Brain region Bromodeoxyuridine Cell Count Cell Nucleus Cell Proliferation Cell physiology Cells Central cord canal structure Cerebral Ventricles Cerebrospinal Fluid Characteristics Cilia Circadian Rhythms Complex Conscious Data Dependovirus Detection Development Disease Electrons Embryo Ependymal Cell Ependymoma Excision Exhibits Floor Fourth ventricle structure Functional disorder Gene Expression Gene Expression Profiling Generations Genetic Growth Half-Life Homeostasis Human Hydrocephalus Knowledge Label Laboratories Life Link Location Malignant Neoplasms Mediating Metabolic Diseases Microscopy Molecular Molecular Profiling Mus Natural regeneration Neuroglia Neurons Organelles Pathway interactions Play Population Population Dynamics Proliferating Property Regenerative capacity Regulation Role Sensory Signal Pathway Signal Transduction Signaling Molecule Sleep Speed Structure Testing Third ventricle structure Time Ventricular Work adult neurogenesis adult stem cell alertness base blood glucose regulation brain parenchyma cell motility cell type cerebrospinal fluid flow ciliopathy cilium motility feeding kinetosome lateral ventricle mRNA sequencing migration molecular marker nerve stem cell neuroblast neurogenesis neuron regeneration novel postnatal prevent progenitor promoter stem cell niche stem cells subventricular zone transcriptome sequencing ultra high resolution ventricular system

项目摘要

PROJECT SUMMARY The laboratory has identified a novel type of ependymal cell (E2) that has two long cilia anchored by two basal bodies that are 30-100 fold larger than those in other cells (Mirzadeh et al. 2008, 2017). E2 cells are found in strategic locations of the ventricular system, next to Neural Stem Cells (NSCs) in the walls of the lateral ventricle and in regions of the third and fourth ventricle critical to feeding and glucose regulation, circadian rhythms, consciousness, alertness and sleep (Mirzadeh et al. 2017). Interestingly, E2-like cells have been also observed in ependymomas, suggesting a link to proliferating progenitors and cancer (Alfaro-Cervelló et al. 2015; Ho, Caccamo, and Garcia 1994). E2 cells' genetic profile, the composition and organization of their unique cilia and basal bodies, their developmental origin, their regenerative capacity, and their function are not known. Ependymal (E) cells remain one of the least understood glial cell types in the brain, yet these cells are involved in functions that are essential for proper brain function. Multiciliated ependymal (E1) cells, through the coordinated beating of their ~50 motile cilia, contribute to cerebrospinal fluid (CSF) flow, and are required to prevent hydrocephalus (Jiménez et al. 2014; Ohata and Alvarez-Buylla 2016; Banizs et al. 2005). In the lateral ventricles, E cells contribute to the regulation of adult neural stem cells (NSCs) and neuronal migration in the largest germinal zone of the adult brain: the ventricular-subventricular zone (V-SVZ). How E cells sense and transmit CSF signals to this germinal niche remains unknown. It is unlikely that E2 cells through their two cilia contribute significantly to CSF flow. Instead, we propose that E2 cilia and basal body could play a key role in the detection of CSF signals. Their location at the interface between the CSF and important brain regions strongly suggests they have pivotal, as-yet unidentified, roles in brain function. Surprisingly, preliminary data indicate that the lateral ventricle E2 cells are relatively short-lived, decrease in number with age, and are constantly regenerated in adult mice. We propose to: 1) characterize E2 cells and their cilia and basal bodies using single cell gene expression analysis, electron and ultra-high resolution microscopy; 2) determine the development and adult population dynamics of E2 cells, and identify the progenitor cells giving rise to new E2 cells in the adult (preliminary evidence suggests that E2 cells are derived from adult NSCs); and 3) investigate whether E2 cell cilia signaling modulates adult stem cell niche function, using conditional deletion of a key cilia signaling molecule enriched in E2 cells. This new knowledge will be essential to decipher the function of E2 cells in the adult V-SVZ. In addition, molecular markers and signaling pathways identified in E2 cells could help understand the cell of origin and growth control of some ependymomas. Given the presence of E2 cells in the third and fourth ventricles, and central canal, next to regions of great functional importance, this new understanding will also help studies of E cell function throughout the brain.

项目概要该实验室已鉴定出一种新型室管膜细胞 (E2)，其具有由两个基底锚定的两个长纤毛。细胞体比其他细胞大 30-100 倍（Mirzadeh 等人，2008，2017）。心室系统的战略位置，紧邻侧脑室壁中的神经干细胞 (NSC) 心室以及对进食和血糖调节、昼夜节律至关重要的第三和第四脑室区域节律、意识、警觉性和睡眠（Mirzadeh 等人，2017）暗示，E2 样细胞也受到影响。在室管膜瘤中观察到，这表明与增殖的祖细胞和癌症有关（Alfaro-Cervelló 等，2017）。 2015；Ho、Caccamo 和 Garcia 1994）。独特的纤毛和基底体、它们的发育起源、它们的再生能力和它们的功能不是室管膜 (E) 细胞仍然是大脑中最不为人所知的神经胶质细胞类型之一，但这些细胞是已知的。通过多纤毛室管膜 (E1) 细胞参与正常大脑功能所必需的功能。约 50 个活动纤毛协调跳动，有助于脑脊液 (CSF) 流动，并且需要预防脑积水（Jiménez 等人，2014 年；Ohata 和 Alvarez-Buylla，2016 年；Banizs 等人，2005 年）。脑室中，E 细胞有助于调节成体神经干细胞 (NSC) 和神经迁移成人大脑最大的生发区：脑室-脑室下区 (V-SVZ) E 细胞如何感知和感知。 E2 细胞不太可能通过其两个纤毛将 CSF 信号传递至该生发生态位。相反，我们认为 E2 纤毛和基底体可能在其中发挥关键作用。脑脊液信号的检测它们位于脑脊液和重要大脑区域之间的界面。令人惊讶的是，初步数据强烈表明它们在大脑功能中具有关键的、尚未确定的作用。表明侧脑室E2细胞寿命相对较短，数量随着年龄的增长而减少，并且我们建议：1）表征 E2 细胞及其纤毛和基底体。使用单细胞基因表达分析、电子和超高分辨率显微镜2)确定 E2 细胞的发育和成体动态，并鉴定产生新 E2 的祖细胞成人细胞（初步证据表明 E2 细胞源自成人 NSC）；3) 进行研究 E2细胞纤毛信号传导是否通过条件性删除关键纤毛来调节成体干细胞生态位功能 E2细胞中富集的信号分子对于破译E2的功能至关重要。此外，在 E2 细胞中鉴定的分子标记和信号通路可能会有所帮助。鉴于 E2 细胞的存在，了解一些室管膜瘤的细胞起源和生长控制。第三脑室和第四脑室以及中央管，毗邻具有重要功能的区域，这个新的了解也将有助于研究整个大脑的 E 细胞功能。