Specification of Peripheral Olfactory Stem Cells

外周嗅觉干细胞的规格

• 批准号: 8336866
• 负责人: ANTHONY S LAMANTIA
• 金额: $ 33.68万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8336866
• 关键词: Accounting; Adult; Afferent Neurons; Alzheimer' s Disease; Autistic Disorder; Basal Cell; Biological; Cells; Characteristics; Code; Consensus; DNA Binding; Data; Disease; Embryo; Environmental Exposure; Feeding behaviors; Foundations; Genes; Genetic; Genetic Transcription; Gonadotropin Hormone Releasing Hormone; Hypothalamic structure; In Vitro; Investigation; Life; Mediating; Mental disorders; Molecular; Molecular Genetics; Monitor; Mutate; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neurosecretory Systems; Olfactory Epithelium; Parkinson Disease; Pathology; Peripheral; Population; Publishing; Recording of previous events; Regulation; Reproduction; Reproductive Behavior; Role; Schizophrenia; Sensory; Signal Transduction; Site; Smell Perception; Social Behavior; Social Interaction; Source; Stem cells; Supporting Cell; Toxic effect; Transcriptional Regulation; Tretinoin; Variant; base; defined contribution; feeding; histogenesis; in vivo; insight; nerve stem cell; nervous system disorder; neurogenesis; neuronal replacement; progenitor; receptor; relating to nervous system; research study; self-renewal; stem; stem cell niche; tissue repair; transcription factor

ABSTRACT Stem cells in the embryonic vertebrate olfactory epithelium (OE) generate critical peripheral chemosensory and central neuroendocrine neurons-essential for feeding, social interactions, and reproduction. Nevertheless, mechanisms for establishing and maintaining these embryonic OE stem cells remain unknown. The progeny of embryonic OE stem cells are retained as progenitors throughout life to constantly replace OE chemosensory neurons; however the relationship between embryonic and adult OE stem cells is largely unexplored. We have recently defined apparent stem and transit amplifying cell populations in the embryonic OE. Apparent embryonic OE stem cells express high levels of the transcription factor Meis1 as well as low levels of Sox2, divide slowly and symmetrically, and are necessary for the genesis of olfactory and vomeronasal receptor neurons (ORNs, VRNs) and gonadotropin releasing hormone (GnRH) neurons-the OE neuronal lineage. The apparent transit amplifying cells express neurogenic bHLH genes including Ascl1 as well as high levels of Sox2, undergo rapid terminal neurogenic divisions, and expand numbers of ORNs, VRNs and GnRH neurons. We will now establish transcription regulatory and signaling mechanisms that determine the identity, proliferative capacity, and progression of OE stem or transit amplifying cells through the OE neurogenic lineage. We will determine how embryonic OE stem or transit amplifying cells with distinct transcriptional and signaling histories give rise to precursor populations established in the embryonic OE and retained in the adult to generate ORNs and VRNs throughout life. Specific Aim 1 will define differential influences of transcriptional regulators on OE stem versus transit amplifying cells. Specific Aim 2 will establish molecular mechanisms that underlie a transcription regulatory network essential for OE stem cell identity and lineage progression. Specific Aim 3 will establish the role of local signaling in defining and maintaining a niche for embryonic OE stem cells. Specific Aim 4 will relate the identity of subsets of embryonic OE stem and transit amplifying cells to adult OE progenitor populations. Our experiments therefore provide a mechanistic account of how OE stem cells are established, and how they are regulated to generate ORNs, VRNs and GnRH neurons. The data provide insight into how stem cells in specific niches mediate histogenesis and tissue repair. Our investigation of molecular mechanisms underlying OE stem cell regulation will also identify potential targets for degenerative change associated with diminished olfaction in a number of neurological and psychiatric disorders including Parkinson's and Alzheimer's diseases as well as schizophrenia.

抽象的 胚胎脊椎动物嗅上皮 (OE) 中的干细胞产生关键的外周化学感觉和 中枢神经内分泌神经元——对于进食、社交和繁殖至关重要。尽管如此， 建立和维持这些胚胎 OE 干细胞的机制仍然未知。的后代 胚胎 OE 干细胞作为祖细胞终生保留，不断取代 OE 化学感应细胞 神经元；然而，胚胎和成体 OE 干细胞之间的关系很大程度上尚未被探索。我们有 最近定义了胚胎 OE 中的表观干细胞和转运扩增细胞群。明显 胚胎 OE 干细胞表达高水平的转录因子 Meis1 以及低水平的 Sox2， 缓慢且对称地分裂，对于嗅觉和犁鼻受体的发生是必需的 神经元（ORN、VRN）和促性腺激素释放激素（GnRH）神经元 - OE 神经元谱系。这 表观转运放大细胞表达神经源性 bHLH 基因，包括 Ascl1 以及高水平的 Sox2 经历快速的终末神经原性分裂，并增加 ORN、VRN 和 GnRH 神经元的数量。 我们现在将建立决定身份的转录调控和信号传导机制， OE 干细胞或转运扩增细胞通过 OE 神经源的增殖能力和进展 血统。我们将确定胚胎 OE 干细胞或转运扩增细胞如何具有不同的转录和 信号传导历史导致在胚胎 OE 中建立并保留在成人中的前体群体 在整个生命过程中生成 ORN 和 VRN。具体目标 1 将定义转录的不同影响 OE 干细胞与转运扩增细胞的调节因子。具体目标 2 将建立分子机制 是对 OE 干细胞身份和谱系进展至关重要的转录调控网络的基础。具体的 目标 3 将确定局部信号传导在定义和维持胚胎 OE 干细胞生态位中的作用。 具体目标 4 将胚胎 OE 干细胞和转运扩增细胞亚群的身份与成人 OE 联系起来 祖先群体。因此，我们的实验提供了 OE 干细胞如何发生的机制解释。 建立，以及如何调节它们产生 ORN、VRN 和 GnRH 神经元。数据提供 深入了解特定生态位中的干细胞如何介导组织发生和组织修复。我们的调查 OE干细胞调节的分子机制也将确定退行性病变的潜在靶点 与许多神经和精神疾病中的嗅觉减弱相关的变化，包括 帕金森病和阿尔茨海默病以及精神分裂症。