Specification of Peripheral Olfactory Stem Cells

外周嗅觉干细胞的规格

• 批准号: 8519102
• 负责人: ANTHONY S LAMANTIA
• 金额: $ 32万
• 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/8519102
• 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.

摘要