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：
10618162
负责人：
Arturo Alvarez-Buylla
金额：
$ 44.15万
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/10618162
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 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 novel postnatal prevent progenitor promoter stem cell niche stem cells subventricular zone transcriptome sequencing transmission process 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.

项目摘要该实验室已经确定了一种新型的室心室细胞（E2），该细胞具有两个长的纤毛，由两个基本锚定比其他细胞中的体积大30-100倍（Mirzadeh等，2008，2017）。在心室系统的战略位置，毗邻后来的神经干细胞（NSC）心室以及第三和第四脑室的区域，对喂食和葡萄糖调节至关重要，昼夜节律节奏，意识，机敏和睡眠（Mirzadeh等，2017）。有趣的是，E2样细胞也已经在室系膜瘤中观察到，这表明与祖细胞和癌症有联系（Alfaro-Cervelló等。 2015; Ho，Caccamo和Garcia 1994）。 E2细胞的遗传特征，其组成和组织独特的纤毛和基本身体，其发育起源，其再生能力及其功能不是已知。室室室（E）细胞仍然是大脑中最知名的神经胶质细胞类型之一，但这些细胞是参与适当大脑功能至关重要的功能。通过多细胞膜膜（E1）细胞通过约50纤毛的协调跳动，有助于脑脊液（CSF）流动，需要预防脑积水（Jiménez等，2014； Ohta和Alvarez-Buylla 2016; Banizs等，2005）。在侧面心室，E细胞有助于调节成年神经元干细胞（NSC）和神经元迁移成人大脑最大的生发带：心室 - 畸形区（V-SVZ）。 E细胞的感知和向该生发生态位传输CSF信号仍然未知。 E2细胞通过其两个纤毛不可能对CSF流量有显着贡献。相反，我们建议E2纤毛和基本身体在检测CSF信号。它们位于CSF和重要大脑区域之间的界面强烈表明它们在大脑功能中具有关键，尚未确定的角色。令人惊讶的是，初步数据表明横向通气E2细胞相对短暂，随着年龄的增长而减少，并且成年小鼠不断再生。我们建议：1）表征E2细胞及其纤毛和基本物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细胞的开发和成人人群动力学，并鉴定祖细胞产生新的E2 成人的细胞（初步证据表明E2细胞源自成年NSC）。 3）调查 E2细胞纤毛信号传导是否使用钥匙纤毛的条件缺失调节成人干细胞生态位功能信号分子富含E2细胞。这种新知识对于破译E2的功能至关重要成年V-SVZ中的细胞。另外，在E2细胞中鉴定出的分子标记和信号通路可能有助于了解某些室系室的起源和生长控制细胞。鉴于在第三和第四个心室以及中央运河，毗邻功能非常重要的区域，这个新的理解还将帮助研究整个大脑的E细胞功能。