Specification of Peripheral Olfactory Stem Cells

摘要 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受和 中枢神经内分泌神经元--对进食、社会互动和生殖至关重要。然而，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干细胞在整个生命中作为祖细胞保留，以不断取代OE化学感受性细胞。 然而，胚胎和成人OE干细胞之间的关系在很大程度上是未探索的。我们有 最近定义的胚胎OE中明显的干细胞和转运扩增细胞群。 胚胎OE干细胞表达高水平的转录因子Meis 1以及低水平的Sox 2， 缓慢而对称地分裂，是嗅觉和犁鼻受体发生所必需的 神经元（ORN，VRNs）和促性腺激素释放激素（GnRH）神经元-OE神经元谱系。的 表观转运放大细胞表达神经源性bHLH基因，包括Ascl 1以及高水平的 Sox 2进行快速的终末神经原性分裂，并扩增ORN、VRN和GnRH神经元的数量。 我们现在将建立转录调节和信号传导机制，以确定身份， 增殖能力，以及OE干细胞或转运扩增细胞通过OE神经源性 脉我们将确定胚胎OE干细胞或转运扩增细胞如何具有不同的转录和 信号历史产生了在胚胎OE中建立并保留在成人中的前体群体 来产生ORN和VRN。具体目标1将定义转录的差异影响， 调节因子对OE干细胞和转运放大细胞的影响。具体目标2将建立分子机制， 是OE干细胞身份和谱系进展所必需的转录调控网络的基础。具体 目的3将建立在定义和维持一个生态位的胚胎OE干细胞的局部信号的作用。 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，我们的实验提供了一个OE干细胞是如何被激活的机制。 建立，以及它们如何被调节以产生ORN，VRN和GnRH神经元。这些数据提供 深入了解特定小生境中的干细胞如何介导组织发生和组织修复。我们调查 OE干细胞调控的分子机制也将确定退行性变的潜在靶点。 在许多神经和精神疾病中与嗅觉减退相关的变化，包括 帕金森氏症和老年痴呆症以及精神分裂症。

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.