PROGRAMS OF GENE EXPRESSION IN OLFACTORY NEUROGENESIS

嗅觉神经发生中的基因表达程序

• 批准号: 6992760
• 负责人: JOHN J. NGAI
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992760
• 关键词: biotechnology; cell differentiation; clone cells; gene expression; gene expression profiling; genetic mapping; high throughput technology; in situ hybridization; laboratory mouse; method development; microarray technology; neurogenesis; neurogenetics; olfactory lobe; respiratory epithelium; stem cells

DESCRIPTION (provided by applicant): The generation of neuronal diversity in the nervous system is a complex process involving the specification and differentiation of a multitude of cellular lineages. Successive developmental programs control the determination and proliferation of individual neuronal types, cell migration, axon extension, and ultimately the formation of functional synaptic connections. Most of these steps are controlled by specific gene expression programs, such as cell fate decisions that lead to the generation of neuronal precursors. The genetic programs underlying the differentiation of mature neurons from their progenitors remain largely unknown, however, in part because of the difficulty in studying neuronal stem cells in their native environments. In the vertebrate olfactory system, primary sensory neurons are continuously regenerated throughout adult life via the proliferation and differentiation of neural progenitor cells. This feature makes the olfactory system particularly amenable for studies on the properties of neuronal stem cells. While some stages of this lineage have been identified with a limited set of molecular markers, the genetic programs that both define and regulate olfactory neurogenesis remain largely unknown. The enormous complexity inherent in this biological problem demands a global view of gene expression in order to fully understand the genetic networks underlying neural function and development in this developmental system. In this application we propose a suite of DNA microarray-based techniques to identify - on a global scale - patterns of gene expression corresponding to distinct stages of the olfactory neuron lineage. We propose (1) to perform temporal profiling of gene expression in olfactory epithelium during embryonic development and lesion-induced regeneration to identify the genes and gene expression programs associated with distinct stages of this lineage, including the earliest multipotent progenitor stage; and (2) to refine this analysis by comparing gene expression patterns in mutants known to disrupt olfactory neurogenesis, and to validate the microarray-based predictions by RNA in situ hybridizations. Our approach is expected to yield highly detailed information about the molecules and pathways responsible for the genesis of olfactory sensory neurons from their progenitor cells. In addition, a broader panel of molecular markers will be generated for distinct stages of olfactory neurogenesis. The elucidation of these, qenetic programs at the genome-wide level will provide valuable insights into the properties of progenitor stem cells from a variety of neural and non-neural systems.

描述（由申请人提供）：神经系统中神经元多样性的产生是一个复杂的过程，涉及多种细胞谱系的规范和分化。连续的发展计划控制单个神经元类型，细胞迁移，轴突扩展以及最终形成功能突触连接的确定和增殖。这些步骤中的大多数都由特定的基因表达程序控制，例如导致神经元前体产生的细胞命运决策。然而，成熟神经元与祖细胞分化的遗传程序基本上是未知的，部分原因是由于难以在其天然环境中研究神经元干细胞。 在脊椎动物嗅觉系统中，原发性感觉神经元通过神经祖细胞的增殖和分化在整个成人生活中连续再生。此功能使嗅觉系统特别适合研究神经元干细胞的性质。尽管该谱系的某些阶段已被识别为有限的分子标记，但定义和调节嗅觉神经发生的遗传程序仍然在很大程度上未知。这个生物学问题固有的巨大复杂性需要全球对基因表达的看法，以便充分了解这种发育系统中神经功能和发展的遗传网络。 在此应用中，我们提出了一套基于DNA微阵列的技术，以在全球尺度上识别与嗅觉神经元谱系不同阶段相对应的基因表达模式。我们建议（1）在胚胎发育和病变诱导的再生过程中对基因表达进行时间分析，以识别与该谱系不同阶段相关的基因和基因表达程序，包括最早的多型祖细胞阶段； （2）通过比较已知破坏嗅觉神经发生的突变体中的基因表达模式，并通过原位杂交验证RNA基于微阵列的预测。 我们的方法有望产生有关导致其祖细胞嗅觉感觉神经元起源的分子和途径的高度详细信息。此外，将生成更广泛的分子标记物，以实现嗅觉神经发生的不同阶段。在全基因组水平上阐明这些Qenetic程序将为各种神经和非神经系统的祖细胞的特性提供宝贵的见解。