Specification of Peripheral Olfactory Stem Cells

摘要 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觉和 中枢神经内分泌神经元--摄食、社会互动和繁殖所必需的。不过， 建立和维持这些胚胎OE干细胞的机制尚不清楚。的后代 胚胎OE干细胞在一生中作为祖细胞保留下来，以不断取代OE化学感受器 然而，胚胎和成年OE干细胞之间的关系在很大程度上还没有被探索。我们有 最近定义了胚胎OE中的表观干细胞和运输放大细胞群。表观 胚胎OE干细胞表达高水平的转录因子Meis1和低水平的Sox2， 缓慢而对称地分裂，是嗅觉和犁鼻感受器发生所必需的 神经元(Ons，VRN)和促性腺激素释放激素(GnRH)神经元-OE神经元谱系。这个 表观转运扩增细胞表达包括Ascl1在内的神经源性bHLH基因，以及高水平的 SOX2，经历快速的终末神经原分裂，并扩大Ons、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来确定身份， 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 信号历史导致在胚胎OE中建立并保留在成体中的前体种群 以在一生中产生兽人和野人。具体目标1将定义转录的不同影响 OE干细胞与转运放大细胞的调节器。特殊目标2将建立分子机制， 转录调控网络是OE干细胞识别和谱系发展所必需的。特定的 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人OE联系起来 祖代种群。因此，我们的实验提供了一种机制，解释了OE干细胞是如何 以及它们如何被调控以产生On、VRN和GnRH神经元。这些数据提供了 洞察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干细胞调控的分子机制也将确定退行性变的潜在靶点 一些神经和精神疾病中与嗅觉减弱相关的变化，包括 帕金森氏症、阿尔茨海默氏症以及精神分裂症。

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.