Specification of Peripheral Olfactory Stem Cells

描述(申请人提供)：胚胎脊椎动物嗅觉上皮(OE)中的干细胞产生关键的外周化学感受器和中枢神经内分泌神经元--对进食、社会互动和繁殖至关重要。然而，建立和维持这些胚胎OE干细胞的机制仍然不清楚。胚胎OE干细胞的后代在一生中作为祖细胞被保留下来，以不断地取代OE化学感觉神经元；然而，胚胎OE干细胞与成年OE干细胞之间的关系在很大程度上是未知的。我们最近在胚胎OE中定义了明显的干细胞和转运性放大细胞群。表观的胚胎OE干细胞表达高水平的转录因子Meis1和低水平的Sox2，分裂缓慢且对称，对于嗅觉和犁鼻感受器神经元(Ons，VRN)和促性腺激素释放激素(GnRH)神经元-OE神经元的起源是必需的。表观传递扩增细胞表达包括Ascl1在内的神经源性bHLH基因和高水平的Sox2，经历快速的神经源性终末分裂，并扩大Orns、VRN和GnRH神经元的数量。我们现在将建立转录调控和信号机制，以确定OE干细胞或转运放大细胞通过OE神经性谱系的身份、增殖能力和进展。我们将确定具有不同转录和信号历史的胚胎OE干细胞或转运扩增细胞如何产生在胚胎OE中建立并在成年后保留的前体群体，以在整个生命过程中产生ON和VRN。具体目标1将确定转录调控因子对OE干细胞和转运体扩增细胞的不同影响。特定目标2将建立转录调控网络的分子机制，该网络对于OE干细胞的识别和谱系发展至关重要。具体目标3将确定局部信号在定义和维持胚胎OE干细胞的生态位中的作用。具体目标4将把胚胎OE干细胞和过渡扩增细胞亚群的特性与成年OE祖细胞群体联系起来。因此，我们的实验提供了一种机制，说明了OE干细胞是如何建立的，以及它们是如何被调控来生成Ons、VRN和GnRH神经元的。这些数据提供了对特定利基中的干细胞如何介导组织发生和组织修复的洞察。我们对OE干细胞调控的分子机制的研究还将确定一些神经和精神疾病，包括帕金森氏症和阿尔茨海默病以及精神分裂症中与嗅觉减少相关的退行性变化的潜在靶点。 与公共健康相关：嗅觉上皮(OE)中的神经干细胞在胚胎中产生，并在整个生命周期中保留，以制造对嗅觉、进食、社会互动和繁殖必不可少的神经元。这些干细胞可能会在几种神经退行性疾病中受损，在这些疾病中，嗅觉缺陷是疾病的早期指标。该项目将确定定义胚胎OE干细胞的分子机制，调控嗅觉神经元的终生发生，并可能成为神经和精神疾病的致病靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Neural stem cells in the olfactory epithelium (OE) arise in the embryo and are retained throughout life to make neurons that are essential for smell, feeding, social interactions and reproduction. These stem cells may be compromised in several neurodegenerative conditions in which olfactory deficits are early indicators of disease. This project will identify molecular mechanisms that define embryonic OE stem cells, regulate lifelong genesis of olfactory neurons, and are likely pathogenic targets for neurological and psychiatric diseases.