Programs of Gene Expression in Olfactory Neurogenesis

项目总结 神经系统中神经元多样性的产生需要指定和区分一个 大量的细胞谱系。连续的发育程序控制着个体的生成 神经元类型、细胞迁移、轴突延伸，最终形成功能性突触连接。 成熟神经元与其祖细胞分化的特定遗传程序仍然存在 特征不完全，部分原因是很难研究其天然的神经前体细胞 环境。同样，成人神经系统损伤后组织再生的机制 是不完全理解的。 在脊椎动物嗅觉系统中，初级感觉神经元和其他类型的细胞不断再生 在整个成年生活中，通过多潜能神经前体细胞的增殖和分化。此功能 使嗅觉系统特别适合于成人神经干细胞特性的研究。 在导致嗅觉上皮中所有成熟神经元和支持细胞被破坏的损伤之后， 成体干细胞被激活，以重建该结构中的所有细胞类型。特别值得关注的是 支持损伤后嗅觉上皮再生的机制及其是否和如何 不同于正常情况下维持组织动态平衡的机制。对这些问题的解释 调节网络对于了解神经元和非神经元细胞类型的成熟程度至关重要 由嗅觉上皮的成体组织干细胞产生。 在这一应用中，我们建议研究细胞机制和遗传途径，以辅助 嗅觉上皮损伤后的重建。具体地说，我们提出了一套独特的方法 包括结合严格的统计分析的单细胞转录组图谱，体内谱系追踪， 和遗传扰动，以(1)阐明伤害诱导再生的潜在机制 嗅觉上皮干细胞巢和(2)建立规范的Wnt信号和Sox2在早期的作用 嗅觉神经发生。这些研究将为理解这些机制提供一个模型。 调节其他神经干细胞类型，为未来治疗和治疗的发展奠定基础 改善神经组织损伤和变性的治疗方法。

PROJECT SUMMARY The generation of neuronal diversity in the nervous system requires the specification and differentiation of a multitude of cellular lineages. Successive developmental programs control the generation of individual neuronal types, cell migration, axon extension, and ultimately the formation of functional synaptic connections. The specific genetic programs underlying the differentiation of mature neurons from their progenitors remain incompletely characterized, in part because of the difficulty in studying neuronal progenitor cells in their native environments. Similarly, mechanisms enabling tissue regeneration following injury in the adult nervous sysem are incompletely understood. In the vertebrate olfactory system, primary sensory neurons and other cell types are continuously regenerated throughout adult life via the proliferation and differentiation of multipotent neural progenitor cells. This feature makes the olfactory system particularly amenable for studies on the properties of adult neural stem cells. Following injury that results in destruction of all mature neurons and support cells in the olfactory epithelium, adult stem cells are activated to reconstitute all cell types in this structure. Of particular interest are the mechanisms that support regeneration of the olfactory epithelium following injury and whether and how they differ from mechanisms subserving tissue homeostasis under normal conditions. Elucidation of these regulatory networks is critical for understanding how mature neuronal and non-neuronal cell types are generated from the adult tissue stem cell of the olfactory epithelium. In this application we propose to investigate the cellular mechanisms and genetic pathways subserving the reconstitution of the olfactory epithelium following injury. Specifically, we propose a unique suite of approaches including single cell transcriptome profiling combined with rigorous statistical analysis, in vivo lineage tracing, and genetic pertubations to (1) elucidate the mechanisms underlying injury-induced regeneration in the olfactory epithelium stem cell niche and (2) establish the roles of canonical Wnt signaling and Sox2 in early olfactory neurogenesis. Together these investigations will provide a model for understanding the mechanisms regulating other neural stem cell types and lay the groundwork for the future development of treatments and therapeutics to ameliorate neural tissue damage and degeneration.